RBCC Red Blood Cell Collection

COL1A1 [Confidence: low (only semi-automatic identification from reviews)]
Collagen alpha-1(I) chain (Alpha-1 type I collagen; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P02452
ID CO1A1_HUMAN Reviewed; 1464 AA.
AC P02452; O76045; P78441; Q13896; Q13902; Q13903; Q14037; Q14992;
read moreAC Q15176; Q15201; Q16050; Q59F64; Q7KZ30; Q7KZ34; Q8IVI5; Q8N473;
AC Q9UML6; Q9UMM7;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 5.
DT 22-JAN-2014, entry version 182.
DE RecName: Full=Collagen alpha-1(I) chain;
DE AltName: Full=Alpha-1 type I collagen;
DE Flags: Precursor;
GN Name=COL1A1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS ALA-1019; ALA-1075; LYS-1391
RP AND SER-1434.
RA Dalgleish R.;
RL Submitted (JUL-1996) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ALA-1075 AND LYS-1391.
RX PubMed=9443882; DOI=10.1086/301689;
RA Korkko J.M., Ala-Kokko L., De Paepe A., Nuytinck L., Earley J.J.,
RA Prockop D.J.;
RT "Analysis of the COL1A1 and COL1A2 genes by PCR amplification and
RT scanning by conformation-sensitive gel electrophoresis identifies only
RT COL1A1 mutations in 15 patients with osteogenesis imperfecta type I:
RT identification of common sequences of null-allele mutations.";
RL Am. J. Hum. Genet. 62:98-110(1998).
RN [3]
RP SEQUENCE REVISION TO 1049.
RA Korkko J.M., Earley J.J., Nuytinck L., DePaepe A., Prockop D.J.,
RA Ala-Kokko L.;
RL Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ALA-1075.
RC TISSUE=Spleen;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS ALA-1075;
RP ARG-1438 AND HIS-1460.
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-589.
RX PubMed=2843432; DOI=10.1016/0378-1119(88)90013-3;
RA D'Alessio M., Bernard M.P., Pretorius P.J., de Wet W., Ramirez F.,
RA Pretorious P.J.;
RT "Complete nucleotide sequence of the region encompassing the first
RT twenty-five exons of the human pro alpha 1(I) collagen gene
RT (COL1A1).";
RL Gene 67:105-115(1988).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-472.
RX PubMed=3178743;
RA Tromp G., Kuivaniemi H., Stacey A., Shikata H., Baldwin C.T.,
RA Jaenisch R., Prockup D.J.;
RT "Structure of a full-length cDNA clone for the prepro alpha 1(I) chain
RT of human type I procollagen.";
RL Biochem. J. 253:919-922(1988).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-181.
RX PubMed=6462220; DOI=10.1038/310337a0;
RA Chu M.-L., de Wet W.J., Bernard M.P., Ding J.-F., Morabito M.,
RA Myers J., Williams C., Ramirez F.;
RT "Human pro alpha 1(I) collagen gene structure reveals evolutionary
RT conservation of a pattern of introns and exons.";
RL Nature 310:337-340(1984).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-44.
RX PubMed=2822714;
RA Rossouw C.M.S., Vergeer W.P., du Plooy S.J., Bernard M.P., Ramirez F.,
RA de Wet W.;
RT "DNA sequences in the first intron of the human pro-alpha 1(I)
RT collagen gene enhance transcription.";
RL J. Biol. Chem. 262:15151-15157(1987).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-34.
RX PubMed=2857713;
RA Chu M.-L., de Wet W., Bernard M.P., Ramirez F.;
RT "Fine structural analysis of the human pro-alpha 1 (I) collagen gene.
RT Promoter structure, AluI repeats, and polymorphic transcripts.";
RL J. Biol. Chem. 260:2315-2320(1985).
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-34.
RX PubMed=3480516; DOI=10.1073/pnas.84.24.8869;
RA Bornstein P., McKay J., Morishima J.K., Devarayalu S., Gelinas R.E.;
RT "Regulatory elements in the first intron contribute to transcriptional
RT control of the human alpha 1(I) collagen gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:8869-8873(1987).
RN [12]
RP PROTEIN SEQUENCE OF 33-52.
RX PubMed=2318855;
RA Wirtz M.K., Keene D.R., Hori H., Glanville R.W., Steinmann B.,
RA Rao V.H., Hollister D.W.;
RT "In vivo and in vitro noncovalent association of excised alpha 1 (I)
RT amino-terminal propeptides with mutant pN alpha 2(I) collagen chains
RT in native mutant collagen in a case of Ehlers-Danlos syndrome, type
RT VII.";
RL J. Biol. Chem. 265:6312-6317(1990).
RN [13]
RP NUCLEOTIDE SEQUENCE OF 156-183.
RX PubMed=2767050;
RA Weil D., D'Alessio M., Ramirez F., de Wet W., Cole W.G., Chan D.,
RA Bateman J.F.;
RT "A base substitution in the exon of a collagen gene causes alternative
RT splicing and generates a structurally abnormal polypeptide in a
RT patient with Ehlers-Danlos syndrome type VII.";
RL EMBO J. 8:1705-1710(1989).
RN [14]
RP PROTEIN SEQUENCE OF 162-301, ALLYSINE AT LYS-170, AND PYROGLUTAMATE
RP FORMATION AT GLN-162.
RC TISSUE=Skin;
RX PubMed=5529814; DOI=10.1021/bi00826a012;
RA Click E.M., Bornstein P.;
RT "Isolation and characterization of the cyanogen bromide peptides from
RT the alpha 1 and alpha 2 chains of human skin collagen.";
RL Biochemistry 9:4699-4706(1970).
RN [15]
RP PROTEIN SEQUENCE OF 175-187 AND 274-289.
RX PubMed=2169412; DOI=10.1111/j.1432-1033.1990.tb19208.x;
RA Baetge B., Notbohm H., Diebold J., Lehmann H., Bodo M., Deutzmann R.,
RA Muller P.K.;
RT "A critical crosslink region in human-bone-derived collagen type I.
RT Specific cleavage site at residue Leu95.";
RL Eur. J. Biochem. 192:153-159(1990).
RN [16]
RP PROTEIN SEQUENCE OF 263-268.
RC TISSUE=Skin;
RX PubMed=4319110;
RA Morgan P.H., Jacobs H.G., Segrest J.P., Cunningham L.W.;
RT "A comparative study of glycopeptides derived from selected vertebrate
RT collagens. A possible role of the carbohydrate in fibril formation.";
RL J. Biol. Chem. 245:5042-5048(1970).
RN [17]
RP NUCLEOTIDE SEQUENCE OF 281-302; 402-420; 823-842; 924-944; 1026-1045
RP AND 1143-1162.
RX PubMed=2374517;
RA Labhard M.E., Hollister D.W.;
RT "Segmental amplification of the entire helical and telopeptide regions
RT of the cDNA for human alpha 1 (I) collagen.";
RL Matrix 10:124-130(1990).
RN [18]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 425-1464, AND VARIANTS ALA-1019 AND
RP ALA-1075.
RX PubMed=6689127; DOI=10.1021/bi00291a023;
RA Bernard M.P., Chu M.-L., Myers J.C., Ramirez F., Eikenberry E.F.,
RA Prockop D.J.;
RT "Nucleotide sequences of complementary deoxyribonucleic acids for the
RT pro alpha 1 chain of human type I procollagen. Statistical evaluation
RT of structures that are conserved during evolution.";
RL Biochemistry 22:5213-5223(1983).
RN [19]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 425-490; 965-1024; 999-1039 AND
RP 1453-1464.
RX PubMed=6183642; DOI=10.1093/nar/10.19.5925;
RA Chu M.-L., Myers J.C., Bernard M.P., Ding J.-F., Ramirez F.;
RT "Cloning and characterization of five overlapping cDNAs specific for
RT the human pro alpha 1(I) collagen chain.";
RL Nucleic Acids Res. 10:5925-5934(1982).
RN [20]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 472-607.
RX PubMed=2981843;
RA Chu M.-L., Gargiulo V., Williams C.J., Ramirez F.;
RT "Multiexon deletion in an osteogenesis imperfecta variant with
RT increased type III collagen mRNA.";
RL J. Biol. Chem. 260:691-694(1985).
RN [21]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 488-625.
RX PubMed=3857621; DOI=10.1073/pnas.82.9.2870;
RA Barsh G.S., Roush C.L., Bonadio J., Byers P.H., Gelinas R.E.;
RT "Intron-mediated recombination may cause a deletion in an alpha 1 type
RT I collagen chain in a lethal form of osteogenesis imperfecta.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:2870-2874(1985).
RN [22]
RP NUCLEOTIDE SEQUENCE OF 710-745, AND VARIANT OI2 ARG-728.
RX PubMed=2339700;
RA Wallis G.A., Starman B.J., Zinn A.B., Byers P.H.;
RT "Variable expression of osteogenesis imperfecta in a nuclear family is
RT explained by somatic mosaicism for a lethal point mutation in the
RT alpha 1(I) gene (COL1A1) of type I collagen in a parent.";
RL Am. J. Hum. Genet. 46:1034-1040(1990).
RN [23]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 746-781, AND VARIANT OI3 SER-767.
RX PubMed=7881420; DOI=10.1093/hmg/3.12.2201;
RA Forlino A., Zolezzi F., Valli M., Pignatti P.F., Cetta G.,
RA Brunelli P.C., Mottes M.;
RT "Severe (type III) osteogenesis imperfecta due to glycine
RT substitutions in the central domain of the collagen triple helix.";
RL Hum. Mol. Genet. 3:2201-2206(1994).
RN [24]
RP PROTEIN SEQUENCE OF 1063-1084, MASS SPECTROMETRY, AND VARIANT
RP ALA-1075.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [25]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1179-1464, VARIANTS OI2 HIS-1277;
RP ARG-1388 AND 1337-GLU-TYR-1338 DEL, AND VARIANTS THR-1251 AND
RP SER-1434.
RX PubMed=8349697;
RA Chessler S.D., Wallis G.A., Byers P.H.;
RT "Mutations in the carboxyl-terminal propeptide of the pro alpha 1(I)
RT chain of type I collagen result in defective chain association and
RT produce lethal osteogenesis imperfecta.";
RL J. Biol. Chem. 268:18218-18225(1993).
RN [26]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1187-1220, AND VARIANT CYS-1195.
RX PubMed=3170557;
RA Cohn D.H., Apone S., Eyre D.R., Starman B.J., Andreassen P.,
RA Charbonneau H., Nicholls A.C., Pope F.M., Byers P.H.;
RT "Substitution of cysteine for glycine within the carboxyl-terminal
RT telopeptide of the alpha 1 chain of type I collagen produces mild
RT osteogenesis imperfecta.";
RL J. Biol. Chem. 263:14605-14607(1988).
RN [27]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1229-1454, AND VARIANT LYS-1391.
RC TISSUE=Bone;
RX PubMed=3340531; DOI=10.1093/nar/16.1.349;
RA Maekelae J.K., Raassina M., Virta A., Vuorio E.;
RT "Human pro alpha 1(I) collagen: cDNA sequence for the C-propeptide
RT domain.";
RL Nucleic Acids Res. 16:349-349(1988).
RN [28]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1440-1464.
RX PubMed=2295701; DOI=10.1172/JCI114424;
RA Willing M.C., Cohn D.H., Byers P.H.;
RT "Frameshift mutation near the 3' end of the COL1A1 gene of type I
RT collagen predicts an elongated Pro alpha 1(I) chain and results in
RT osteogenesis imperfecta type I.";
RL J. Clin. Invest. 85:282-290(1990).
RN [29]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1454-1464, AND VARIANT ALA-1075.
RX PubMed=1995349; DOI=10.1016/0014-5793(91)80237-W;
RA Maatta A., Bornstein P., Penttinen R.P.;
RT "Highly conserved sequences in the 3'-untranslated region of the
RT COL1A1 gene bind cell-specific nuclear proteins.";
RL FEBS Lett. 279:9-13(1991).
RN [30]
RP REVIEW ON VARIANTS.
RX PubMed=2010058;
RA Kuivaniemi H., Tromp G., Prockop D.J.;
RT "Mutations in collagen genes: causes of rare and some common diseases
RT in humans.";
RL FASEB J. 5:2052-2060(1991).
RN [31]
RP REVIEW ON VARIANTS.
RX PubMed=9101290;
RX DOI=10.1002/(SICI)1098-1004(1997)9:4<300::AID-HUMU2>3.3.CO;2-8;
RA Kuivaniemi H., Tromp G., Prockop D.J.;
RT "Mutations in fibrillar collagens (types I, II, III, and XI), fibril-
RT associated collagen (type IX), and network-forming collagen (type X)
RT cause a spectrum of diseases of bone, cartilage, and blood vessels.";
RL Hum. Mutat. 9:300-315(1997).
RN [32]
RP REVIEW ON VARIANTS.
RX PubMed=1895312;
RA Byers P.H., Wallis G.A., Willing M.C.;
RT "Osteogenesis imperfecta: translation of mutation to phenotype.";
RL J. Med. Genet. 28:433-442(1991).
RN [33]
RP INTERACTION WITH TRAM2.
RX PubMed=14749390; DOI=10.1128/MCB.24.4.1758-1768.2004;
RA Stefanovic B., Stefanovic L., Schnabl B., Bataller R., Brenner D.A.;
RT "TRAM2 protein interacts with endoplasmic reticulum Ca2+ pump Serca2b
RT and is necessary for collagen type I synthesis.";
RL Mol. Cell. Biol. 24:1758-1768(2004).
RN [34]
RP VARIANT OI2 CYS-1166.
RX PubMed=3016737; DOI=10.1073/pnas.83.16.6045;
RA Cohn D.H., Byers P.H., Steinmann B., Gelinas R.E.;
RT "Lethal osteogenesis imperfecta resulting from a single nucleotide
RT change in one human pro alpha 1(I) collagen allele.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:6045-6047(1986).
RN [35]
RP VARIANT OI2 ARG-569.
RX PubMed=3108247;
RA Bateman J.F., Chan D., Walkers I.D., Rogers J.G., Cole W.G.;
RT "Lethal perinatal osteogenesis imperfecta due to the substitution of
RT arginine for glycine at residue 391 of the alpha 1(I) chain of type I
RT collagen.";
RL J. Biol. Chem. 262:7021-7027(1987).
RN [36]
RP VARIANT OI2 CYS-926.
RX PubMed=3667599;
RA Vogel B.E., Minor R.R., Freund M., Prockop D.J.;
RT "A point mutation in a type I procollagen gene converts glycine 748 of
RT the alpha 1 chain to cysteine and destabilizes the triple helix in a
RT lethal variant of osteogenesis imperfecta.";
RL J. Biol. Chem. 262:14737-14744(1987).
RN [37]
RP VARIANT OI2 ARG-842.
RX PubMed=3403550;
RA Bateman J.F., Lamande S.R., Dahl H.-H.M., Chan D., Cole W.G.;
RT "Substitution of arginine for glycine 664 in the collagen alpha 1(I)
RT chain in lethal perinatal osteogenesis imperfecta. Demonstration of
RT the peptide defect by in vitro expression of the mutant cDNA.";
RL J. Biol. Chem. 263:11627-11630(1988).
RN [38]
RP VARIANT OI1 CYS-1195.
RX PubMed=3244312;
RA Labhard M.E., Wirtz M.K., Pope F.M., Nicholls A.C., Hollister D.W.;
RT "A cysteine for glycine substitution at position 1017 in an alpha 1(I)
RT chain of type I collagen in a patient with mild dominantly inherited
RT osteogenesis imperfecta.";
RL Mol. Biol. Med. 5:197-207(1988).
RN [39]
RP VARIANT OI2 VAL-434.
RX PubMed=2470760;
RA Patterson E., Smiley E., Bonadio J.;
RT "RNA sequence analysis of a perinatal lethal osteogenesis imperfecta
RT mutation.";
RL J. Biol. Chem. 264:10083-10087(1989).
RN [40]
RP VARIANT OI4 SER-1010.
RX PubMed=2745420;
RA Marini J.C., Grange D.K., Gottesman G.S., Lewis M.B., Koeplin D.A.;
RT "Osteogenesis imperfecta type IV. Detection of a point mutation in one
RT alpha 1(I) collagen allele (COL1A1) by RNA/RNA hybrid analysis.";
RL J. Biol. Chem. 264:11893-11900(1989).
RN [41]
RP VARIANTS OI2 ALA-1106; VAL-1151; ARG-1154 AND VAL-1184.
RX PubMed=2777764;
RA Lamande S.R., Dahl H.-H.M., Cole W.G., Bateman J.F.;
RT "Characterization of point mutations in the collagen COL1A1 and COL1A2
RT genes causing lethal perinatal osteogenesis imperfecta.";
RL J. Biol. Chem. 264:15809-15812(1989).
RN [42]
RP VARIANT OI3 SER-1022.
RX PubMed=2511192;
RA Pack M., Constantinou C.D., Kalia K., Nielsen K.B., Prockop D.J.;
RT "Substitution of serine for alpha 1(I)-glycine 844 in a severe variant
RT of osteogenesis imperfecta minimally destabilizes the triple helix of
RT type I procollagen. The effects of glycine substitutions on thermal
RT stability are either position of amino acid specific.";
RL J. Biol. Chem. 264:19694-19699(1989).
RN [43]
RP VARIANT OI2 CYS-1082.
RX PubMed=2913053; DOI=10.1172/JCI113920;
RA Constantinou C.D., Nielsen K.B., Prockop D.J.;
RT "A lethal variant of osteogenesis imperfecta has a single base
RT mutation that substitutes cysteine for glycine 904 of the alpha 1(I)
RT chain of type I procollagen. The asymptomatic mother has an
RT unidentified mutation producing an overmodified and unstable type I
RT procollagen.";
RL J. Clin. Invest. 83:574-584(1989).
RN [44]
RP VARIANT OI1 CYS-272, VARIANT OI3 CYS-704, AND VARIANT OI2 CYS-896.
RX PubMed=2794057; DOI=10.1172/JCI114286;
RA Starman B.J., Eyre D.R., Charbonneau H., Harrylock M., Weis M.A.,
RA Weiss L., Graham J.M. Jr., Byers P.H.;
RT "Osteogenesis imperfecta. The position of substitution for glycine by
RT cysteine in the triple helical domain of the pro alpha 1(I) chains of
RT type I collagen determines the clinical phenotype.";
RL J. Clin. Invest. 84:1206-1214(1989).
RN [45]
RP VARIANT OI2 CYS-422.
RA Fertala A., Westerhausen A., Morris G.M., Rooney J.E., Prockop D.J.;
RT "Two cysteine substitutions in the type I procollagen genes (COL1A1
RT and COL1A2) that cause lethal osteogenesis imperfecta. The location of
RT glycine substitutions does not in any simple way predict their effects
RT on protein function or phenotype.";
RL Am. J. Hum. Genet. 47:A216-A216(1990).
RN [46]
RP VARIANTS OI2 SER-776 AND SER-809.
RX PubMed=2116413;
RA Westerhausen A., Kishi J., Prockop D.J.;
RT "Mutations that substitute serine for glycine alpha 1-598 and glycine
RT alpha 1-631 in type I procollagen. The effects on thermal unfolding of
RT the triple helix are position-specific and demonstrate that the
RT protein unfolds through a series of cooperative blocks.";
RL J. Biol. Chem. 265:13995-14000(1990).
RN [47]
RP VARIANT OI2 ARG-1025.
RX PubMed=2211725;
RA Wallis G.A., Starman B.J., Schwartz M.F., Byers P.H.;
RT "Substitution of arginine for glycine at position 847 in the triple-
RT helical domain of the alpha 1 (I) chain of type I collagen produces
RT lethal osteogenesis imperfecta. Molecules that contain one or two
RT abnormal chains differ in stability and secretion.";
RL J. Biol. Chem. 265:18628-18633(1990).
RN [48]
RP VARIANTS OI2 SER-1091; SER-1181; SER-1187 AND VAL-1187.
RA Cohn D.H., Wallis G.A., Zhang X., Byers P.H.;
RT "Serine for glycine substitutions in the alpha1(I) chain of type I
RT collagen: biological plasticity in the Gly-Pro-Hyp clamp at the
RT carboxyl-terminal end of triple helicalH domain.";
RL Matrix 10:236-236(1990).
RN [49]
RP VARIANT OI2 ASP-719.
RX PubMed=2035536;
RA Zhuang J., Constantinou C.D., Ganguly A., Prockop D.J.;
RT "A single base mutation in type I procollagen (COL1A1) that converts
RT glycine alpha 1-541 to aspartate in a lethal variant of osteogenesis
RT imperfecta: detection of the mutation with a carbodiimide reaction of
RT DNA heteroduplexes and direct sequencing of products of the PCR.";
RL Am. J. Hum. Genet. 48:1186-1191(1991).
RN [50]
RP VARIANT OI2 CYS-869.
RX PubMed=1953667;
RA Steinmann B., Westerhausen A., Constantinou C.D., Superti-Furga A.,
RA Prockop D.J.;
RT "Substitution of cysteine for glycine-alpha 1-691 in the pro alpha
RT 1(I) chain of type I procollagen in a proband with lethal osteogenesis
RT imperfecta destabilizes the triple helix at a site C-terminal to the
RT substitution.";
RL Biochem. J. 279:747-752(1991).
RN [51]
RP VARIANT OI2 CYS-926.
RX PubMed=2036375; DOI=10.1021/bi00234a035;
RA Kadler K.E., Torre-Blanco A., Adachi E., Vogel B.E., Hojima Y.,
RA Prockop D.J.;
RT "A type I collagen with substitution of a cysteine for glycine-748 in
RT the alpha 1(I) chain copolymerizes with normal type I collagen and can
RT generate fractallike structures.";
RL Biochemistry 30:5081-5088(1991).
RN [52]
RP VARIANT OI3 ARG-332, AND VARIANT OI2 SER-1181.
RX PubMed=2037280; DOI=10.1007/BF01213088;
RA Pruchno C.J., Cohn D.H., Wallis G.A., Willing M.C., Starman B.J.,
RA Zhang X., Byers P.H.;
RT "Osteogenesis imperfecta due to recurrent point mutations at CpG
RT dinucleotides in the COL1A1 gene of type I collagen.";
RL Hum. Genet. 87:33-40(1991).
RN [53]
RP VARIANT OI4 CYS-356.
RX PubMed=1988452;
RA Valli M., Mottes M., Tenni R., Sangalli A., Gomez Lira M., Rossi A.,
RA Antoniazzi F., Cetta G., Pignatti P.F.;
RT "A de novo G to T transversion in a pro-alpha 1 (I) collagen gene for
RT a moderate case of osteogenesis imperfecta. Substitution of cysteine
RT for glycine 178 in the triple helical domain.";
RL J. Biol. Chem. 266:1872-1878(1991).
RN [54]
RP VARIANT OI2 VAL-815.
RX PubMed=1874719;
RA Tsuneyoshi T., Westerhausen A., Constantinou C.D., Prockop D.J.;
RT "Substitutions for glycine alpha 1-637 and glycine alpha 2-694 of type
RT I procollagen in lethal osteogenesis imperfecta. The conformational
RT strain on the triple helix introduced by a glycine substitution can be
RT transmitted along the helix.";
RL J. Biol. Chem. 266:15608-15613(1991).
RN [55]
RP VARIANT OI1 ARG-263.
RX PubMed=1718984;
RA Deak S.B., Scholz P.M., Amenta P.S., Constantinou C.D.,
RA Levi-Minzi S.A., Gonzalez-Lavin L., MacKenzie J.W.;
RT "The substitution of arginine for glycine 85 of the alpha 1(I)
RT procollagen chain results in mild osteogenesis imperfecta. The
RT mutation provides direct evidence for three discrete domains of
RT cooperative melting of intact type I collagen.";
RL J. Biol. Chem. 266:21827-21832(1991).
RN [56]
RP VARIANT OI2 1046-GLY--PRO-1048 DEL.
RX PubMed=1939261;
RA Hawkins J.R., Superti-Furga A., Steinmann B., Dalgleish R.;
RT "A 9-base pair deletion in COL1A1 in a lethal variant of osteogenesis
RT imperfecta.";
RL J. Biol. Chem. 266:22370-22374(1991).
RN [57]
RP VARIANT OI3 CYS-593, AND VARIANT OI4 CYS-593.
RX PubMed=1770532;
RA Nicholls A.C., Oliver J.E., Renouf D.V., Keston M., Pope F.M.;
RT "Substitution of cysteine for glycine at residue 415 of one allele of
RT the alpha 1(I) chain of type I procollagen in type III/IV osteogenesis
RT imperfecta.";
RL J. Med. Genet. 28:757-764(1991).
RN [58]
RP VARIANT ALA-1075.
RX PubMed=1870989; DOI=10.1093/nar/19.15.4302;
RA Sokolov B.P., Constantinou C.D., Tsuneyoshi T., Zhuang J.,
RA Prockop D.J.;
RT "G to A polymorphism in exon 45 of the COL1A1 gene.";
RL Nucleic Acids Res. 19:4302-4302(1991).
RN [59]
RP VARIANT OI1 SER-1079.
RX PubMed=1634225; DOI=10.1007/BF00219169;
RA Mottes M., Sangalli A., Valli M., Gomez Lira M., Tenni R.,
RA Buttitta P., Pignatti P.F., Cetta G.;
RT "Mild dominant osteogenesis imperfecta with intrafamilial variability:
RT the cause is a serine for glycine alpha 1(I) 901 substitution in a
RT type-I collagen gene.";
RL Hum. Genet. 89:480-484(1992).
RN [60]
RP VARIANT OI2 VAL-980.
RX PubMed=1511982; DOI=10.1007/BF00221955;
RA Bonaventure J., Cohen-Solal L., Lasselin C., Maroteaux P.;
RT "A dominant mutation in the COL1A1 gene that substitutes glycine for
RT valine causes recurrent lethal osteogenesis imperfecta.";
RL Hum. Genet. 89:640-646(1992).
RN [61]
RP VARIANT OI2 1046-GLY--PRO-1048 DEL.
RX PubMed=1460047;
RA Wallis G.A., Kadler K.E., Starman B.J., Byers P.H.;
RT "A tripeptide deletion in the triple-helical domain of the pro alpha
RT 1(I) chain of type I procollagen in a patient with lethal osteogenesis
RT imperfecta does not alter cleavage of the molecule by N-proteinase.";
RL J. Biol. Chem. 267:25529-25534(1992).
RN [62]
RP VARIANT OI1 CYS-221.
RX PubMed=1737847; DOI=10.1172/JCI115622;
RA Shapiro J.R., Stover M.L., Burn V.E., McKinstry M.B., Burshell A.L.,
RA Chipman S.D., Rowe D.W.;
RT "An osteopenic nonfracture syndrome with features of mild osteogenesis
RT imperfecta associated with the substitution of a cysteine for glycine
RT at triple helix position 43 in the pro alpha 1(I) chain of type I
RT collagen.";
RL J. Clin. Invest. 89:567-573(1992).
RN [63]
RP VARIANTS OI2 VAL-434; VAL-1151 AND VAL-1184.
RX PubMed=1613761;
RA Cole W.G., Patterson E., Bonadio J., Campbell P.E., Fortune D.W.;
RT "The clinicopathological features of three babies with osteogenesis
RT imperfecta resulting from the substitution of glycine by valine in the
RT pro alpha 1 (I) chain of type I procollagen.";
RL J. Med. Genet. 29:112-118(1992).
RN [64]
RP VARIANT OI2 CYS-1312.
RX PubMed=8456808; DOI=10.1002/ajmg.1320450216;
RA Bateman J.F., Lamande S.R., Hannagan M., Moeller I., Dahl H.-H.M.,
RA Cole W.G.;
RT "Chemical cleavage method for the detection of RNA base changes:
RT experience in the application to collagen mutations in osteogenesis
RT imperfecta.";
RL Am. J. Med. Genet. 45:233-240(1993).
RN [65]
RP VARIANT OI3 SER-530.
RX PubMed=8456809; DOI=10.1002/ajmg.1320450217;
RA Marini J.C., Lewis M.B., Chen K.J.;
RT "Moderately severe osteogenesis imperfecta associated with
RT substitutions of serine for glycine in the alpha 1(I) chain of type I
RT collagen.";
RL Am. J. Med. Genet. 45:241-245(1993).
RN [66]
RP VARIANT OI4 CYS-353.
RX PubMed=8339541;
RA Wirtz M.K., Rao V.H., Glanville R.W., Labhard M.E., Pretorius P.J.,
RA de Vries W.N., de Wet W., Hollister D.W.;
RT "A cysteine for glycine substitution at position 175 in an alpha 1 (I)
RT chain of type I collagen produces a clinically heterogeneous form of
RT osteogenesis imperfecta.";
RL Connect. Tissue Res. 29:1-11(1993).
RN [67]
RP VARIANT OI2 ALA-1088.
RX PubMed=7679635; DOI=10.1111/j.1432-1033.1993.tb17565.x;
RA Valli M., Sangalli A., Rossi A., Mottes M., Forlino A., Tenni R.,
RA Pignatti P.F., Cetta G.;
RT "Osteogenesis imperfecta and type-I collagen mutations. A lethal
RT variant caused by a Gly910-->Ala substitution in the alpha 1 (I)
RT chain.";
RL Eur. J. Biochem. 211:415-419(1993).
RN [68]
RP VARIANT OI1 VAL-263.
RX PubMed=8223589; DOI=10.1111/j.1432-1033.1993.tb18220.x;
RA Valli M., Zolezzi F., Mottes M., Antoniazzi F., Stanzial F., Tenni R.,
RA Pignatti P.F., Cetta G.;
RT "Gly85 to Val substitution in pro alpha 1(I) chain causes mild
RT osteogenesis imperfecta and introduces a susceptibility to protease
RT digestion.";
RL Eur. J. Biochem. 217:77-82(1993).
RN [69]
RP VARIANT OI2 VAL-743.
RX PubMed=8100209; DOI=10.1007/BF00217768;
RA Mackay K., Lund A.M., Raghunath M., Steinmann B., Dalgleish R.;
RT "SSCP detection of a Gly565Val substitution in the pro alpha 1(I)
RT collagen chain resulting in osteogenesis imperfecta type II.";
RL Hum. Genet. 91:439-444(1993).
RN [70]
RP VARIANTS OI2 SER-425 AND SER-530, VARIANT OI4 SER-560, VARIANT OI3
RP SER-719, AND VARIANT ALA-823.
RX PubMed=7691343; DOI=10.1093/hmg/2.8.1155;
RA Mackay K., Byers P.H., Dalgleish R.;
RT "An RT-PCR-SSCP screening strategy for detection of mutations in the
RT gene encoding the alpha 1 chain of type I collagen: application to
RT four patients with osteogenesis imperfecta.";
RL Hum. Mol. Genet. 2:1155-1160(1993).
RN [71]
RP VARIANT OI2 SER-593, AND VARIANT OI3 SER-593.
RX PubMed=8364588; DOI=10.1002/humu.1380020308;
RA Mottes M., Gomez Lira M., Valli M., Scarano G., Lonardo F.,
RA Forlino A., Cetta G., Pignatti P.F.;
RT "Paternal mosaicism for a COL1A1 dominant mutation (alpha 1 Ser-415)
RT causes recurrent osteogenesis imperfecta.";
RL Hum. Mutat. 2:196-204(1993).
RN [72]
RP VARIANT OI4 SER-530.
RX PubMed=8094076;
RA Marini J.C., Lewis M.B., Wang Q., Chen K.J., Orrison B.M.;
RT "Serine for glycine substitutions in type I collagen in two cases of
RT type IV osteogenesis imperfecta (OI). Additional evidence for a
RT regional model of OI pathophysiology.";
RL J. Biol. Chem. 268:2667-2673(1993).
RN [73]
RP VARIANTS OI2.
RX PubMed=8349698;
RA Chessler S.D., Byers P.H.;
RT "BiP binds type I procollagen pro alpha chains with mutations in the
RT carboxyl-terminal propeptide synthesized by cells from patients with
RT osteogenesis imperfecta.";
RL J. Biol. Chem. 268:18226-18233(1993).
RN [74]
RP VARIANT OI2 ARG-389.
RX PubMed=7520724; DOI=10.1016/8756-3282(94)90295-X;
RA Sztrolovics R., Glorieux F.H., Travers R., van der Rest M.,
RA Roughley P.J.;
RT "Osteogenesis imperfecta: comparison of molecular defects with bone
RT histological changes.";
RL Bone 15:321-328(1994).
RN [75]
RP VARIANT OI3 ARG-350.
RX PubMed=8019571; DOI=10.1002/humu.1380030327;
RA Mackay K., de Paepe A., Nuytinck L., Dalgleish R.;
RT "Substitution of glycine-172 by arginine in the alpha 1 chain of type
RT I collagen in a patient with osteogenesis imperfecta, type III.";
RL Hum. Mutat. 3:324-326(1994).
RN [76]
RP VARIANT OI2 CYS-1124.
RX PubMed=7961597;
RA Kurosaka D., Hattori S., Hori H., Yamaguchi N., Hasegawa T.,
RA Akimoto H., Nagai Y.;
RT "Substitution of cysteine for glycine-946 in the alpha 1(I) chain of
RT type I procollagen causes lethal osteogenesis imperfecta.";
RL J. Biochem. 115:853-857(1994).
RN [77]
RP VARIANT OI4 SER-1061.
RX PubMed=7982948;
RA Lightfoot S.J., Atkinson M.S., Murphy G., Byers P.H., Kadler K.E.;
RT "Substitution of serine for glycine 883 in the triple helix of the pro
RT alpha 1 (I) chain of type I procollagen produces osteogenesis
RT imperfecta type IV and introduces a structural change in the triple
RT helix that does not alter cleavage of the molecule by procollagen N-
RT proteinase.";
RL J. Biol. Chem. 269:30352-30357(1994).
RN [78]
RP VARIANT OI3 ARG-332.
RX PubMed=8669434;
RX DOI=10.1002/(SICI)1096-8628(19960111)61:2<111::AID-AJMG1>3.0.CO;2-#;
RA Zhuang J., Tromp G., Kuivaniemi H., Castells S., Prockop D.J.;
RT "Substitution of arginine for glycine at position 154 of the alpha 1
RT chain of type I collagen in a variant of osteogenesis imperfecta:
RT comparison to previous cases with the same mutation.";
RL Am. J. Med. Genet. 61:111-116(1996).
RN [79]
RP VARIANT OI2 SER-839.
RX PubMed=8786074; DOI=10.1007/s004390050043;
RA Nuytinck L., Dalgleish R., Spotila L., Renard J.-P.,
RA van Regemorter N., de Paepe A.;
RT "Substitution of glycine-661 by serine in the alpha1(I) and alpha2(I)
RT chains of type I collagen results in different clinical and
RT biochemical phenotypes.";
RL Hum. Genet. 97:324-329(1996).
RN [80]
RP VARIANT OI3 PRO-1464.
RX PubMed=8723681;
RX DOI=10.1002/(SICI)1098-1004(1996)7:4<318::AID-HUMU5>3.3.CO;2-S;
RA Oliver J.E., Thompson E.M., Pope F.M., Nicholls A.C.;
RT "Mutation in the carboxy-terminal propeptide of the Pro alpha 1(I)
RT chain of type I collagen in a child with severe osteogenesis
RT imperfecta (OI type III): possible implications for protein folding.";
RL Hum. Mutat. 7:318-326(1996).
RN [81]
RP INVOLVEMENT IN OSTEOPOROSIS.
RX PubMed=8841196; DOI=10.1038/ng1096-203;
RA Grant S.F.A., Reid D.M., Blake G., Herd R., Fogelman I., Ralston S.H.;
RT "Reduced bone density and osteoporosis associated with a polymorphic
RT Sp1 binding site in the collagen type I alpha 1 gene.";
RL Nat. Genet. 14:203-205(1996).
RN [82]
RP VARIANTS OI3 SER-821; SER-1040; SER-1049; SER-1058 AND SER-1076.
RX PubMed=9101304;
RX DOI=10.1002/(SICI)1098-1004(1997)9:4<378::AID-HUMU16>3.3.CO;2-5;
RA Lund A.M., Skovby F., Schwartz M.;
RT "Serine for glycine substitutions in the C-terminal third of the alpha
RT 1(I) chain of collagen I in five patients with nonlethal osteogenesis
RT imperfecta.";
RL Hum. Mutat. 9:378-382(1997).
RN [83]
RP VARIANT OI2 VAL-764.
RX PubMed=9143923;
RX DOI=10.1002/(SICI)1098-1004(1997)9:5<431::AID-HUMU9>3.3.CO;2-C;
RA Lund A.M., Skovby F., Schwartz M.;
RT "(G586V) substitutions in the alpha 1 and alpha 2 chains of collagen
RT I: effect of alpha-chain stoichiometry on the phenotype of
RT osteogenesis imperfecta?";
RL Hum. Mutat. 9:431-436(1997).
RN [84]
RP VARIANTS OI4 ALA-398; CYS-527 AND CYS-701.
RX PubMed=9600458;
RX DOI=10.1002/(SICI)1098-1004(1998)11:5<395::AID-HUMU7>3.3.CO;2-W;
RA Sarafova A.P., Choi H., Forlino A., Gajko A., Cabral W.A., Tosi L.,
RA Reing C.M., Marini J.C.;
RT "Three novel type I collagen mutations in osteogenesis imperfecta type
RT IV probands are associated with discrepancies between electrophoretic
RT migration of osteoblast and fibroblast collagen.";
RL Hum. Mutat. 11:395-403(1998).
RN [85]
RP VARIANTS OI2 SER-656 AND ASP-1172.
RX PubMed=10627137;
RX DOI=10.1002/(SICI)1098-1004(1998)12:1<71::AID-HUMU16>3.3.CO;2-W;
RA Mottes M., Gomez Lira M., Zolezzi F., Valli M., Lisi V., Freising P.;
RT "Four new cases of lethal osteogenesis imperfecta due to glycine
RT substitutions in COL1A1 and genes.";
RL Hum. Mutat. 12:71-72(1998).
RN [86]
RP INVOLVEMENT IN INVOLUTIONAL OSTEOPOROSIS.
RX PubMed=9535665; DOI=10.1056/NEJM199804093381502;
RA Uitterlinden A.G., Burger H., Huang Q., Yue F., McGuigan F.E.A.,
RA Grant S.F.A., Hofman A., van Leeuwen J.P.T.M., Pols H.A.P.,
RA Ralston S.H.;
RT "Relation of alleles of the collagen type Ialpha1 gene to bone density
RT and the risk of osteoporotic fractures in postmenopausal women.";
RL N. Engl. J. Med. 338:1016-1021(1998).
RN [87]
RP VARIANT OI3 SER-866.
RX PubMed=10408781;
RX DOI=10.1002/(SICI)1098-1004(1999)13:6<503::AID-HUMU11>3.0.CO;2-L;
RA Lund A.M., Astroem E., Soederhaell S., Schwartz M., Skovby F.;
RT "Osteogenesis imperfecta: mosaicism and refinement of the genotype-
RT phenotype map in OI type III.";
RL Hum. Mutat. 13:503-503(1999).
RN [88]
RP VARIANT EDS1 CYS-312.
RX PubMed=10739762; DOI=10.1086/302859;
RA Nuytinck L., Freund M., Lagae L., Pierard G.E., Hermanns-Le T.,
RA De Paepe A.;
RT "Classical Ehlers-Danlos syndrome caused by a mutation in type I
RT collagen.";
RL Am. J. Hum. Genet. 66:1398-1402(2000).
RN [89]
RP DISEASE, AND CHROMOSOMAL TRANSLOCATION WITH PDGFB.
RX PubMed=8988177; DOI=10.1038/ng0197-95;
RA Simon M.-P., Pedeutour F., Sirvent N., Grosgeorge J., Minoletti F.,
RA Coindre J.-M., Terrier-Lacombe M.-J., Mandahl N., Craver R.D.,
RA Blin N., Sozzi G., Turc-Carel C., O'Brien K.P., Kedra D., Fransson I.,
RA Guilbaud C., Dumanski J.P.;
RT "Deregulation of the platelet-derived growth factor B-chain gene via
RT fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans
RT and giant-cell fibroblastoma.";
RL Nat. Genet. 15:95-98(1997).
RN [90]
RP DISEASE, AND CHROMOSOMAL TRANSLOCATION WITH PDGFB.
RX PubMed=12660034; DOI=10.1016/S0165-4608(02)00844-0;
RA Sandberg A.A., Anderson W.D., Fredenberg C., Hashimoto H.;
RT "Dermatofibrosarcoma protuberans of breast.";
RL Cancer Genet. Cytogenet. 142:56-59(2003).
RN [91]
RP VARIANT CAFFD CYS-1014.
RX PubMed=15864348; DOI=10.1172/JCI22760;
RA Gensure R.C., Maekitie O., Barclay C., Chan C., Depalma S.R.,
RA Bastepe M., Abuzahra H., Couper R., Mundlos S., Sillence D.,
RA Ala-Kokko L., Seidman J.G., Cole W.G., Jueppner H.;
RT "A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey
RT disease) expands the spectrum of collagen-related disorders.";
RL J. Clin. Invest. 115:1250-1257(2005).
RN [92]
RP VARIANTS OI3 VAL-203 AND SER-821, AND VARIANTS OI4 ARG-257 AND
RP SER-683.
RX PubMed=16879195; DOI=10.1111/j.1399-0004.2006.00646.x;
RA Venturi G., Tedeschi E., Mottes M., Valli M., Camilot M., Viglio S.,
RA Antoniazzi F., Tato L.;
RT "Osteogenesis imperfecta: clinical, biochemical and molecular
RT findings.";
RL Clin. Genet. 70:131-139(2006).
RN [93]
RP VARIANTS OI1/OI3/OI4 ARG-194; ASP-242; ARG-257; SER-722; SER-767;
RP SER-821 AND SER-1058.
RX PubMed=16705691; DOI=10.1002/humu.9423;
RA Lee K.S., Song H.R., Cho T.J., Kim H.J., Lee T.M., Jin H.S.,
RA Park H.Y., Kang S., Jung S.C., Koo S.K.;
RT "Mutational spectrum of type I collagen genes in Korean patients with
RT osteogenesis imperfecta.";
RL Hum. Mutat. 27:599-599(2006).
RN [94]
RP VARIANTS OI2 ARG-22; ARG-581; VAL-734 AND ASN-1413, VARIANTS OI4
RP ARG-197 AND CYS-338, VARIANTS OI1 VAL-320; ARG-555; SER-647 AND
RP GLU-1219, AND VARIANTS ALA-205; LYS-288; SER-906 AND HIS-1356.
RX PubMed=16786509; DOI=10.1002/humu.9430;
RA Pollitt R., McMahon R., Nunn J., Bamford R., Afifi A., Bishop N.,
RA Dalton A.;
RT "Mutation analysis of COL1A1 and COL1A2 in patients diagnosed with
RT osteogenesis imperfecta type I-IV.";
RL Hum. Mutat. 27:716-716(2006).
RN [95]
RP VARIANT OI2 ASP-833.
RX PubMed=16566045; DOI=10.1002/pd.1428;
RA Aerts M., Van Holsbeke C., de Ravel T., Devlieger R.;
RT "Prenatal diagnosis of type II osteogenesis imperfecta, describing a
RT new mutation in the COL1A1 gene.";
RL Prenat. Diagn. 26:394-394(2006).
RN [96]
RP VARIANT OI1 ASP-1157.
RX PubMed=16638323;
RA Wang Z., Xu D.L., Chen Z., Hu J.Y., Yang Z., Wang L.T.;
RT "A new mutation in COL1A1 gene in a family with osteogenesis
RT imperfecta.";
RL Zhonghua Yi Xue Za Zhi 86:170-173(2006).
RN [97]
RP VARIANT EDS1 CYS-312, AND VARIANTS CYS-574 AND CYS-1093.
RX PubMed=17211858; DOI=10.1002/humu.20455;
RA Malfait F., Symoens S., De Backer J., Hermanns-Le T., Sakalihasan N.,
RA Lapiere C.M., Coucke P., De Paepe A.;
RT "Three arginine to cysteine substitutions in the pro-alpha (I)-
RT collagen chain cause Ehlers-Danlos syndrome with a propensity to
RT arterial rupture in early adulthood.";
RL Hum. Mutat. 28:387-395(2007).
RN [98]
RP VARIANT CYS-1066.
RX PubMed=17206620; DOI=10.1002/humu.20456;
RA Cabral W.A., Makareeva E., Letocha A.D., Scribanu N., Fertala A.,
RA Steplewski A., Keene D.R., Persikov A.V., Leikin S., Marini J.C.;
RT "Y-position cysteine substitution in type I collagen (alpha1(I)
RT R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-
RT Danlos syndrome phenotype.";
RL Hum. Mutat. 28:396-405(2007).
RN [99]
RP VARIANTS OI1 GLU-266 AND SER-287, AND VARIANT OI4 SER-353.
RX PubMed=17875077; DOI=10.1111/j.1442-200X.2007.02422.x;
RA Kataoka K., Ogura E., Hasegawa K., Inoue M., Seino Y., Morishima T.,
RA Tanaka H.;
RT "Mutations in type I collagen genes in Japanese osteogenesis
RT imperfecta patients.";
RL Pediatr. Int. 49:564-569(2007).
RN [100]
RP VARIANTS ALA-1075; GLN-1141 AND ILE-1177.
RX PubMed=18272325; DOI=10.1016/j.ygeno.2007.12.008;
RA Chan T.F., Poon A., Basu A., Addleman N.R., Chen J., Phong A.,
RA Byers P.H., Klein T.E., Kwok P.Y.;
RT "Natural variation in four human collagen genes across an ethnically
RT diverse population.";
RL Genomics 91:307-314(2008).
RN [101]
RP VARIANTS OI1 VAL-200 AND PHE-349, VARIANT OI2 SER-866, AND VARIANT OI3
RP SER-1040.
RX PubMed=18670065; DOI=10.1007/BF03195625;
RA Witecka J., Augusciak-Duma A.M., Kruczek A., Szydlo A., Lesiak M.,
RA Krzak M., Pietrzyk J.J., Mannikko M., Sieron A.L.;
RT "Two novel COL1A1 mutations in patients with osteogenesis imperfecta
RT (OI) affect the stability of the collagen type I triple-helix.";
RL J. Appl. Genet. 49:283-295(2008).
RN [102]
RP VARIANTS OI2 THR-146; VAL-288; ASP-353; VAL-368; THR-390; SER-425;
RP ASP-455; VAL-470; VAL-509; ALA-548; ARG-602; ASP-605; ARG-614;
RP ARG-740; SER-809; ARG-824; ARG-845; ARG-848; HIS-855; SER-866;
RP SER-875; SER-884; ASP-896; CYS-947; ASP-977; CYS-1001; VAL-1022;
RP ALA-PRO-GLY-1052 INS; ASP-1055; SER-1094; ASP-1100 AND ASN-1413, AND
RP VARIANT ALA-1075.
RX PubMed=18996919; DOI=10.1093/hmg/ddn374;
RA Bodian D.L., Chan T.F., Poon A., Schwarze U., Yang K., Byers P.H.,
RA Kwok P.Y., Klein T.E.;
RT "Mutation and polymorphism spectrum in osteogenesis imperfecta type
RT II: implications for genotype-phenotype relationships.";
RL Hum. Mol. Genet. 18:463-471(2009).
RN [103]
RP VARIANT ASN-1219, AND CHARACTERIZATION OF VARIANT ASN-1219.
RX PubMed=21344539; DOI=10.1002/humu.21475;
RA Lindahl K., Barnes A.M., Fratzl-Zelman N., Whyte M.P., Hefferan T.E.,
RA Makareeva E., Brusel M., Yaszemski M.J., Rubin C.J., Kindmark A.,
RA Roschger P., Klaushofer K., McAlister W.H., Mumm S., Leikin S.,
RA Kessler E., Boskey A.L., Ljunggren O., Marini J.C.;
RT "COL1 C-propeptide cleavage site mutations cause high bone mass
RT osteogenesis imperfecta.";
RL Hum. Mutat. 32:598-609(2011).
CC -!- FUNCTION: Type I collagen is a member of group I collagen
CC (fibrillar forming collagen).
CC -!- SUBUNIT: Trimers of one alpha 2(I) and two alpha 1(I) chains.
CC Interacts with MRC2 (By similarity). Interacts with TRAM2.
CC -!- INTERACTION:
CC O01949:AAEL010235 (xeno); NbExp=5; IntAct=EBI-982999, EBI-7685554;
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular
CC matrix (By similarity).
CC -!- TISSUE SPECIFICITY: Forms the fibrils of tendon, ligaments and
CC bones. In bones the fibrils are mineralized with calcium
CC hydroxyapatite.
CC -!- DOMAIN: The C-terminal propeptide, also known as COLFI domain,
CC have crucial roles in tissue growth and repair by controlling both
CC the intracellular assembly of procollagen molecules and the
CC extracellular assembly of collagen fibrils. It binds a calcium ion
CC which is essential for its function (By similarity).
CC -!- PTM: Proline residues at the third position of the tripeptide
CC repeating unit (G-X-P) are hydroxylated in some or all of the
CC chains. Proline residues at the second position of the tripeptide
CC repeating unit (G-P-X) are hydroxylated in some of the chains.
CC -!- PTM: O-linked glycan consists of a Glc-Gal disaccharide bound to
CC the oxygen atom of a post-translationally added hydroxyl group.
CC -!- DISEASE: Caffey disease (CAFFD) [MIM:114000]: Characterized by an
CC infantile episode of massive subperiosteal new bone formation that
CC typically involves the diaphyses of the long bones, mandible, and
CC clavicles. The involved bones may also appear inflamed, with
CC painful swelling and systemic fever often accompanying the
CC illness. The bone changes usually begin before 5 months of age and
CC resolve before 2 years of age. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Ehlers-Danlos syndrome 1 (EDS1) [MIM:130000]: A
CC connective tissue disorder characterized by hyperextensible skin,
CC atrophic cutaneous scars due to tissue fragility and joint
CC hyperlaxity. EDS1 is the severe form of classic Ehlers-Danlos
CC syndrome. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Ehlers-Danlos syndrome 7A (EDS7A) [MIM:130060]: A
CC connective tissue disorder characterized by hyperextensible skin,
CC atrophic cutaneous scars due to tissue fragility and joint
CC hyperlaxity. Marked by bilateral congenital hip dislocation,
CC hyperlaxity of the joints, and recurrent partial dislocations.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Osteogenesis imperfecta 1 (OI1) [MIM:166200]: An
CC autosomal dominant form of osteogenesis imperfecta, a connective
CC tissue disorder characterized by low bone mass, bone fragility and
CC susceptibility to fractures after minimal trauma. Disease severity
CC ranges from very mild forms without fractures to intrauterine
CC fractures and perinatal lethality. Extraskeletal manifestations,
CC which affect a variable number of patients, are dentinogenesis
CC imperfecta, hearing loss, and blue sclerae. OI1 is a non-deforming
CC form with normal height or mild short stature, and no
CC dentinogenesis imperfecta. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Osteogenesis imperfecta 2 (OI2) [MIM:166210]: An
CC autosomal dominant form of osteogenesis imperfecta, a connective
CC tissue disorder characterized by low bone mass, bone fragility and
CC susceptibility to fractures after minimal trauma. Disease severity
CC ranges from very mild forms without fractures to intrauterine
CC fractures and perinatal lethality. Extraskeletal manifestations,
CC which affect a variable number of patients, are dentinogenesis
CC imperfecta, hearing loss, and blue sclerae. OI2 is characterized
CC by bone fragility, with many perinatal fractures, severe bowing of
CC long bones, undermineralization, and death in the perinatal period
CC due to respiratory insufficiency. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Osteogenesis imperfecta 3 (OI3) [MIM:259420]: An
CC autosomal dominant form of osteogenesis imperfecta, a connective
CC tissue disorder characterized by low bone mass, bone fragility and
CC susceptibility to fractures after minimal trauma. Disease severity
CC ranges from very mild forms without fractures to intrauterine
CC fractures and perinatal lethality. Extraskeletal manifestations,
CC which affect a variable number of patients, are dentinogenesis
CC imperfecta, hearing loss, and blue sclerae. OI3 is characterized
CC by progressively deforming bones, very short stature, a triangular
CC face, severe scoliosis, grayish sclera and dentinogenesis
CC imperfecta. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Osteogenesis imperfecta 4 (OI4) [MIM:166220]: An
CC autosomal dominant form of osteogenesis imperfecta, a connective
CC tissue disorder characterized by low bone mass, bone fragility and
CC susceptibility to fractures after minimal trauma. Disease severity
CC ranges from very mild forms without fractures to intrauterine
CC fractures and perinatal lethality. Extraskeletal manifestations,
CC which affect a variable number of patients, are dentinogenesis
CC imperfecta, hearing loss, and blue sclerae. OI4 is characterized
CC by moderately short stature, mild to moderate scoliosis, grayish
CC or white sclera and dentinogenesis imperfecta. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Osteoporosis (OSTEOP) [MIM:166710]: A systemic skeletal
CC disorder characterized by decreased bone mass and deterioration of
CC bone microarchitecture without alteration in the composition of
CC bone. The result is fragile bones and an increased risk of
CC fractures, even after minimal trauma. Osteoporosis is a chronic
CC condition of multifactorial etiology and is usually clinically
CC silent until a fracture occurs. Note=Disease susceptibility is
CC associated with variations affecting the gene represented in this
CC entry.
CC -!- DISEASE: Note=A chromosomal aberration involving COL1A1 is found
CC in dermatofibrosarcoma protuberans. Translocation
CC t(17;22)(q22;q13) with PDGF.
CC -!- SIMILARITY: Belongs to the fibrillar collagen family.
CC -!- SIMILARITY: Contains 1 fibrillar collagen NC1 domain.
CC -!- SIMILARITY: Contains 1 VWFC domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAD92834.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=Osteogenesis imperfecta variant database;
CC Note=Collagen type I alpha 1 (COL1A1);
CC URL="http://oi.gene.le.ac.uk/home.php?select_db=COL1A1";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/COL1A1ID186.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/COL1A1";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Type-I collagen entry;
CC URL="http://en.wikipedia.org/wiki/Type-I_collagen";
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DR EMBL; Z74615; CAA98968.1; -; mRNA.
DR EMBL; AF017178; AAB94054.3; -; Genomic_DNA.
DR EMBL; AB209597; BAD92834.1; ALT_INIT; mRNA.
DR EMBL; BC036531; AAH36531.1; -; mRNA.
DR EMBL; M20789; AAB59373.1; -; Genomic_DNA.
DR EMBL; M36546; AAA60150.1; -; mRNA.
DR EMBL; X07884; CAA30731.1; -; mRNA.
DR EMBL; X00820; CAA25394.1; -; Genomic_DNA.
DR EMBL; J02829; AAA51993.1; -; Genomic_DNA.
DR EMBL; M10627; AAA51992.1; -; Genomic_DNA.
DR EMBL; J03559; AAA52052.1; -; Genomic_DNA.
DR EMBL; K01228; AAA51995.1; -; mRNA.
DR EMBL; J00110; AAA52289.1; -; mRNA.
DR EMBL; J00111; AAA52290.1; -; mRNA.
DR EMBL; J00112; AAA52291.1; -; mRNA.
DR EMBL; J00113; AAN86574.1; -; mRNA.
DR EMBL; K03179; AAA51847.1; -; Genomic_DNA.
DR EMBL; M11162; AAA75386.1; -; Genomic_DNA.
DR EMBL; L47667; AAB59576.1; -; Genomic_DNA.
DR EMBL; S64596; AAB27856.1; -; mRNA.
DR EMBL; M23213; AAB59363.1; -; Genomic_DNA.
DR EMBL; X06269; CAA29605.1; -; mRNA.
DR EMBL; M32798; AAA52049.1; -; mRNA.
DR EMBL; M55998; AAA52036.1; -; Genomic_DNA.
DR PIR; I60114; CGHU1S.
DR RefSeq; NP_000079.2; NM_000088.3.
DR UniGene; Hs.172928; -.
DR UniGene; Hs.681002; -.
DR PDB; 1Q7D; X-ray; 1.80 A; A/B/C=914-930.
DR PDB; 2LLP; NMR; -; A/B/C=949-965.
DR PDB; 3EJH; X-ray; 2.10 A; E/F=956-977.
DR PDB; 3GXE; X-ray; 2.60 A; E/F=254-275.
DR PDBsum; 1Q7D; -.
DR PDBsum; 2LLP; -.
DR PDBsum; 3EJH; -.
DR PDBsum; 3GXE; -.
DR ProteinModelPortal; P02452; -.
DR SMR; P02452; 1247-1464.
DR DIP; DIP-36077N; -.
DR IntAct; P02452; 13.
DR ChEMBL; CHEMBL2364188; -.
DR DrugBank; DB00048; Collagenase.
DR DrugBank; DB00039; Palifermin.
DR PhosphoSite; P02452; -.
DR DMDM; 296439504; -.
DR DOSAC-COBS-2DPAGE; P02452; -.
DR PaxDb; P02452; -.
DR PRIDE; P02452; -.
DR DNASU; 1277; -.
DR Ensembl; ENST00000225964; ENSP00000225964; ENSG00000108821.
DR GeneID; 1277; -.
DR KEGG; hsa:1277; -.
DR UCSC; uc002iqm.3; human.
DR CTD; 1277; -.
DR GeneCards; GC17M048260; -.
DR HGNC; HGNC:2197; COL1A1.
DR HPA; HPA008405; -.
DR HPA; HPA011795; -.
DR MIM; 114000; phenotype.
DR MIM; 120150; gene.
DR MIM; 130000; phenotype.
DR MIM; 130060; phenotype.
DR MIM; 166200; phenotype.
DR MIM; 166210; phenotype.
DR MIM; 166220; phenotype.
DR MIM; 166710; phenotype.
DR MIM; 259420; phenotype.
DR MIM; 607907; phenotype.
DR neXtProt; NX_P02452; -.
DR Orphanet; 1310; Caffey disease.
DR Orphanet; 31112; Dermatofibrosarcoma protuberans.
DR Orphanet; 90309; Ehlers-Danlos syndrome type 1.
DR Orphanet; 99875; Ehlers-Danlos syndrome type 7A.
DR Orphanet; 230845; Ehlers-Danlos syndrome, vascular-like type.
DR Orphanet; 230857; Ehlers-Danlos/osteogenesis imperfecta syndrome.
DR Orphanet; 314029; High bone mass osteogenesis imperfecta.
DR Orphanet; 216796; Osteogenesis imperfecta type 1.
DR Orphanet; 216804; Osteogenesis imperfecta type 2.
DR Orphanet; 216812; Osteogenesis imperfecta type 3.
DR Orphanet; 216820; Osteogenesis imperfecta type 4.
DR PharmGKB; PA35041; -.
DR eggNOG; NOG12793; -.
DR HOVERGEN; HBG004933; -.
DR InParanoid; P02452; -.
DR KO; K06236; -.
DR OMA; GSTMGTD; -.
DR OrthoDB; EOG7TJ3HH; -.
DR PhylomeDB; P02452; -.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_160300; Binding and Uptake of Ligands by Scavenger Receptors.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; COL1A1; human.
DR EvolutionaryTrace; P02452; -.
DR GeneWiki; Collagen,_type_I,_alpha_1; -.
DR GenomeRNAi; 1277; -.
DR NextBio; 5161; -.
DR PMAP-CutDB; P02452; -.
DR PRO; PR:P02452; -.
DR ArrayExpress; P02452; -.
DR Bgee; P02452; -.
DR Genevestigator; P02452; -.
DR GO; GO:0005584; C:collagen type I; IMP:UniProtKB.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005201; F:extracellular matrix structural constituent; IEA:Ensembl.
DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0048407; F:platelet-derived growth factor binding; IDA:MGI.
DR GO; GO:0001568; P:blood vessel development; IMP:UniProtKB.
DR GO; GO:0060346; P:bone trabecula formation; IEA:Ensembl.
DR GO; GO:0060351; P:cartilage development involved in endochondral bone morphogenesis; IEA:Ensembl.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IEA:Ensembl.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0071300; P:cellular response to retinoic acid; IEA:Ensembl.
DR GO; GO:0071560; P:cellular response to transforming growth factor beta stimulus; IEA:Ensembl.
DR GO; GO:0032964; P:collagen biosynthetic process; IMP:UniProtKB.
DR GO; GO:0030574; P:collagen catabolic process; TAS:Reactome.
DR GO; GO:0030199; P:collagen fibril organization; IMP:UniProtKB.
DR GO; GO:0048706; P:embryonic skeletal system development; IMP:UniProtKB.
DR GO; GO:0001958; P:endochondral ossification; IEA:Ensembl.
DR GO; GO:0022617; P:extracellular matrix disassembly; TAS:Reactome.
DR GO; GO:0060325; P:face morphogenesis; IEA:Ensembl.
DR GO; GO:0001957; P:intramembranous ossification; IEA:Ensembl.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0010812; P:negative regulation of cell-substrate adhesion; IEA:Ensembl.
DR GO; GO:0001649; P:osteoblast differentiation; IEA:Ensembl.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0090263; P:positive regulation of canonical Wnt receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0030335; P:positive regulation of cell migration; IDA:UniProtKB.
DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; IDA:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; IDA:UniProtKB.
DR GO; GO:0070208; P:protein heterotrimerization; IEA:Ensembl.
DR GO; GO:0034504; P:protein localization to nucleus; IDA:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:Ensembl.
DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl.
DR GO; GO:0031960; P:response to corticosteroid stimulus; IEA:Ensembl.
DR GO; GO:0042542; P:response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0043434; P:response to peptide hormone stimulus; IEA:Ensembl.
DR GO; GO:0007605; P:sensory perception of sound; IMP:UniProtKB.
DR GO; GO:0043589; P:skin morphogenesis; IMP:UniProtKB.
DR GO; GO:0034505; P:tooth mineralization; IMP:UniProtKB.
DR GO; GO:0007601; P:visual perception; IMP:UniProtKB.
DR InterPro; IPR008160; Collagen.
DR InterPro; IPR000885; Fib_collagen_C.
DR InterPro; IPR001007; VWF_C.
DR Pfam; PF01410; COLFI; 1.
DR Pfam; PF01391; Collagen; 13.
DR Pfam; PF00093; VWC; 1.
DR ProDom; PD002078; Fib_collagen_C; 1.
DR SMART; SM00038; COLFI; 1.
DR SMART; SM00214; VWC; 1.
DR PROSITE; PS51461; NC1_FIB; 1.
DR PROSITE; PS01208; VWFC_1; 1.
DR PROSITE; PS50184; VWFC_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium; Chromosomal rearrangement; Collagen;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Disulfide bond; Dwarfism; Ehlers-Danlos syndrome;
KW Extracellular matrix; Glycoprotein; Hydroxylation; Metal-binding;
KW Osteogenesis imperfecta; Polymorphism; Pyrrolidone carboxylic acid;
KW Reference proteome; Repeat; Secreted; Signal.
FT SIGNAL 1 22
FT PROPEP 23 161 N-terminal propeptide.
FT /FTId=PRO_0000005719.
FT CHAIN 162 1218 Collagen alpha-1(I) chain.
FT /FTId=PRO_0000005720.
FT PROPEP 1219 1464 C-terminal propeptide.
FT /FTId=PRO_0000005721.
FT DOMAIN 38 96 VWFC.
FT DOMAIN 1229 1464 Fibrillar collagen NC1.
FT REGION 162 178 Nonhelical region (N-terminal).
FT REGION 179 1192 Triple-helical region.
FT REGION 1193 1218 Nonhelical region (C-terminal).
FT MOTIF 745 747 Cell attachment site (Potential).
FT MOTIF 1093 1095 Cell attachment site (Potential).
FT METAL 1277 1277 Calcium (By similarity).
FT METAL 1279 1279 Calcium (By similarity).
FT METAL 1280 1280 Calcium; via carbonyl oxygen (By
FT similarity).
FT METAL 1282 1282 Calcium; via carbonyl oxygen (By
FT similarity).
FT METAL 1285 1285 Calcium (By similarity).
FT SITE 161 162 Cleavage; by procollagen N-endopeptidase.
FT SITE 953 954 Cleavage; by collagenase (By similarity).
FT SITE 1218 1219 Cleavage; by procollagen C-endopeptidase.
FT MOD_RES 162 162 Pyrrolidone carboxylic acid.
FT MOD_RES 170 170 Allysine.
FT MOD_RES 265 265 5-hydroxylysine.
FT MOD_RES 1108 1108 5-hydroxylysine (By similarity).
FT MOD_RES 1164 1164 3-hydroxyproline (By similarity).
FT MOD_RES 1208 1208 Allysine (By similarity).
FT CARBOHYD 265 265 O-linked (Gal...).
FT CARBOHYD 1108 1108 O-linked (Gal...) (By similarity).
FT CARBOHYD 1365 1365 N-linked (GlcNAc...).
FT DISULFID 1259 1291 By similarity.
FT DISULFID 1265 1265 Interchain (By similarity).
FT DISULFID 1282 1282 Interchain (By similarity).
FT DISULFID 1299 1462 By similarity.
FT DISULFID 1370 1415 By similarity.
FT VARIANT 22 22 G -> R (in OI2).
FT /FTId=VAR_063290.
FT VARIANT 146 146 P -> T (in a patient with osteogenesis
FT imperfecta type 2; rare variant of
FT unknown pathological significance).
FT /FTId=VAR_063291.
FT VARIANT 194 194 G -> R (in OI1).
FT /FTId=VAR_063292.
FT VARIANT 197 197 G -> C (in dbSNP:rs8179178).
FT /FTId=VAR_001642.
FT VARIANT 197 197 G -> R (in OI4).
FT /FTId=VAR_063293.
FT VARIANT 200 200 G -> V (in OI1; patient diagnosed with
FT OI1/OI4).
FT /FTId=VAR_063294.
FT VARIANT 203 203 G -> V (in OI3).
FT /FTId=VAR_063295.
FT VARIANT 205 205 P -> A (in dbSNP:rs72667032).
FT /FTId=VAR_001643.
FT VARIANT 221 221 G -> C (in OI1; mild form).
FT /FTId=VAR_001644.
FT VARIANT 224 224 G -> C (in OI1; mild phenotype).
FT /FTId=VAR_001645.
FT VARIANT 242 242 G -> D (in OI).
FT /FTId=VAR_063296.
FT VARIANT 257 257 G -> R (in OI4).
FT /FTId=VAR_063297.
FT VARIANT 263 263 G -> R (in OI1; mild form).
FT /FTId=VAR_001646.
FT VARIANT 263 263 G -> V (in OI1; mild form).
FT /FTId=VAR_001647.
FT VARIANT 266 266 G -> E (in OI1).
FT /FTId=VAR_063298.
FT VARIANT 272 272 G -> C (in OI1).
FT /FTId=VAR_001648.
FT VARIANT 275 275 G -> D (in OI2).
FT /FTId=VAR_001649.
FT VARIANT 287 287 G -> S (in OI1).
FT /FTId=VAR_063299.
FT VARIANT 288 288 E -> K (in a patient with osteogenesis
FT imperfecta type 1 carrying also mutation
FT Glu-1219; unknown pathological
FT significance).
FT /FTId=VAR_063300.
FT VARIANT 288 288 E -> V (in a patient with osteogenesis
FT imperfecta type 2; rare variant of
FT unknown pathological significance).
FT /FTId=VAR_063301.
FT VARIANT 312 312 R -> C (in EDS1).
FT /FTId=VAR_013579.
FT VARIANT 320 320 G -> V (in OI1).
FT /FTId=VAR_063302.
FT VARIANT 332 332 G -> R (in OI3; mild to moderate form).
FT /FTId=VAR_001650.
FT VARIANT 338 338 G -> C (in OI4).
FT /FTId=VAR_063303.
FT VARIANT 349 349 V -> F (in OI1).
FT /FTId=VAR_063304.
FT VARIANT 350 350 G -> R (in OI3).
FT /FTId=VAR_001651.
FT VARIANT 353 353 G -> C (in OI4).
FT /FTId=VAR_001652.
FT VARIANT 353 353 G -> D (in OI2).
FT /FTId=VAR_063305.
FT VARIANT 353 353 G -> S (in OI4).
FT /FTId=VAR_063306.
FT VARIANT 356 356 G -> C (in OI4; mild form).
FT /FTId=VAR_001653.
FT VARIANT 368 368 G -> V (in OI2).
FT /FTId=VAR_063307.
FT VARIANT 383 383 G -> C (in OI4).
FT /FTId=VAR_001654.
FT VARIANT 389 389 G -> C (in OI; moderate form).
FT /FTId=VAR_001655.
FT VARIANT 389 389 G -> R (in OI2).
FT /FTId=VAR_001656.
FT VARIANT 390 390 A -> T (in a patient with osteogenesis
FT imperfecta type 2; rare variant of
FT unknown pathological significance;
FT dbSNP:rs116794104).
FT /FTId=VAR_063308.
FT VARIANT 398 398 G -> A (in OI4).
FT /FTId=VAR_001657.
FT VARIANT 398 398 G -> D (in OI2).
FT /FTId=VAR_001658.
FT VARIANT 401 401 G -> C (in OI4).
FT /FTId=VAR_001659.
FT VARIANT 404 404 G -> C (in OI; moderate form).
FT /FTId=VAR_001660.
FT VARIANT 422 422 G -> C (in OI2).
FT /FTId=VAR_001661.
FT VARIANT 425 425 G -> S (in OI2; lethal form).
FT /FTId=VAR_001662.
FT VARIANT 434 434 G -> V (in OI2).
FT /FTId=VAR_001663.
FT VARIANT 455 455 G -> D (in OI2).
FT /FTId=VAR_063309.
FT VARIANT 470 470 G -> V (in OI2).
FT /FTId=VAR_063310.
FT VARIANT 476 476 G -> R (in OI2; dbSNP:rs57377812).
FT /FTId=VAR_001664.
FT VARIANT 509 509 G -> V (in OI2).
FT /FTId=VAR_063311.
FT VARIANT 527 527 G -> C (in OI4).
FT /FTId=VAR_001665.
FT VARIANT 530 530 G -> S (in OI2, OI3 and OI4; mild to
FT lethal form).
FT /FTId=VAR_001666.
FT VARIANT 533 533 G -> D (in OI2).
FT /FTId=VAR_001667.
FT VARIANT 548 548 G -> A (in OI2).
FT /FTId=VAR_063312.
FT VARIANT 555 555 P -> R (in OI1).
FT /FTId=VAR_063313.
FT VARIANT 560 560 G -> C (in OI4).
FT /FTId=VAR_001669.
FT VARIANT 560 560 G -> R (in OI2).
FT /FTId=VAR_001670.
FT VARIANT 560 560 G -> S (in OI4).
FT /FTId=VAR_001668.
FT VARIANT 564 564 R -> H (in dbSNP:rs1800211).
FT /FTId=VAR_001671.
FT VARIANT 569 569 G -> R (in OI2).
FT /FTId=VAR_001672.
FT VARIANT 574 574 R -> C (in a patient with isolated
FT osteopenia and vascular rupture).
FT /FTId=VAR_063314.
FT VARIANT 581 581 G -> R (in OI2).
FT /FTId=VAR_063315.
FT VARIANT 593 593 G -> C (in OI3 and OI4).
FT /FTId=VAR_001673.
FT VARIANT 593 593 G -> S (in OI2 and OI3; moderate to
FT lethal form).
FT /FTId=VAR_001674.
FT VARIANT 602 602 G -> R (in OI2).
FT /FTId=VAR_063316.
FT VARIANT 605 605 G -> D (in OI2).
FT /FTId=VAR_063317.
FT VARIANT 614 614 G -> R (in OI2).
FT /FTId=VAR_063318.
FT VARIANT 647 647 G -> S (in OI1).
FT /FTId=VAR_063319.
FT VARIANT 656 656 G -> S (in OI2).
FT /FTId=VAR_001676.
FT VARIANT 683 683 G -> S (in OI4).
FT /FTId=VAR_063320.
FT VARIANT 701 701 G -> C (in OI4).
FT /FTId=VAR_001677.
FT VARIANT 704 704 G -> C (in OI3).
FT /FTId=VAR_001678.
FT VARIANT 719 719 G -> D (in OI2).
FT /FTId=VAR_001679.
FT VARIANT 719 719 G -> S (in OI3).
FT /FTId=VAR_001680.
FT VARIANT 722 722 G -> S (in OI1).
FT /FTId=VAR_063321.
FT VARIANT 728 728 G -> R (in OI2).
FT /FTId=VAR_001681.
FT VARIANT 734 734 G -> V (in OI2).
FT /FTId=VAR_063322.
FT VARIANT 737 737 G -> D (in OI2).
FT /FTId=VAR_001682.
FT VARIANT 740 740 G -> R (in OI2).
FT /FTId=VAR_063323.
FT VARIANT 743 743 G -> S (in OI2).
FT /FTId=VAR_001683.
FT VARIANT 743 743 G -> V (in OI2).
FT /FTId=VAR_001684.
FT VARIANT 764 764 G -> V (in OI2).
FT /FTId=VAR_001685.
FT VARIANT 767 767 G -> S (in OI3; severe).
FT /FTId=VAR_001686.
FT VARIANT 776 776 G -> S (in OI2).
FT /FTId=VAR_001687.
FT VARIANT 809 809 G -> S (in OI2).
FT /FTId=VAR_001688.
FT VARIANT 815 815 G -> V (in OI2).
FT /FTId=VAR_001689.
FT VARIANT 821 821 G -> S (in OI3).
FT /FTId=VAR_001690.
FT VARIANT 823 823 P -> A (in dbSNP:rs1800214).
FT /FTId=VAR_001691.
FT VARIANT 824 824 G -> R (in OI2).
FT /FTId=VAR_063324.
FT VARIANT 833 833 G -> D (in OI2).
FT /FTId=VAR_063325.
FT VARIANT 839 839 G -> S (in OI2; mild to moderate form).
FT /FTId=VAR_001692.
FT VARIANT 842 842 G -> R (in OI2).
FT /FTId=VAR_001693.
FT VARIANT 845 845 G -> R (in OI2).
FT /FTId=VAR_001694.
FT VARIANT 848 848 G -> R (in OI2).
FT /FTId=VAR_063342.
FT VARIANT 851 851 G -> D (in OI2).
FT /FTId=VAR_001695.
FT VARIANT 855 855 N -> H (in a patient with osteogenesis
FT imperfecta type 2; rare variant of
FT unknown pathological significance).
FT /FTId=VAR_063326.
FT VARIANT 866 866 G -> S (in OI3 and OI2).
FT /FTId=VAR_008118.
FT VARIANT 869 869 G -> C (in OI2).
FT /FTId=VAR_001696.
FT VARIANT 875 875 G -> S (in OI2).
FT /FTId=VAR_063327.
FT VARIANT 884 884 G -> S (in OI2 and OI3; extremely severe
FT form).
FT /FTId=VAR_001697.
FT VARIANT 896 896 G -> C (in OI2).
FT /FTId=VAR_001698.
FT VARIANT 896 896 G -> D (in OI2).
FT /FTId=VAR_063328.
FT VARIANT 906 906 G -> S (in a patient with mild
FT osteogenesis imperfecta; uncertain
FT pathological significance).
FT /FTId=VAR_063329.
FT VARIANT 926 926 G -> C (in OI2).
FT /FTId=VAR_001699.
FT VARIANT 947 947 G -> C (in OI2).
FT /FTId=VAR_063330.
FT VARIANT 977 977 G -> D (in OI2).
FT /FTId=VAR_063331.
FT VARIANT 980 980 G -> V (in OI2).
FT /FTId=VAR_001700.
FT VARIANT 1001 1001 G -> C (in OI2).
FT /FTId=VAR_063332.
FT VARIANT 1010 1010 G -> S (in OI4).
FT /FTId=VAR_001701.
FT VARIANT 1014 1014 R -> C (in CAFFD).
FT /FTId=VAR_033097.
FT VARIANT 1019 1019 G -> A (in dbSNP:rs1135348).
FT /FTId=VAR_030013.
FT VARIANT 1022 1022 G -> S (in OI3; severe form).
FT /FTId=VAR_001702.
FT VARIANT 1022 1022 G -> V (in OI2).
FT /FTId=VAR_001703.
FT VARIANT 1025 1025 G -> R (in OI2).
FT /FTId=VAR_001704.
FT VARIANT 1040 1040 G -> S (in OI2 and OI3; moderate to
FT lethal form).
FT /FTId=VAR_001705.
FT VARIANT 1043 1043 G -> S (in OI2).
FT /FTId=VAR_001706.
FT VARIANT 1046 1048 Missing (in OI2).
FT /FTId=VAR_001707.
FT VARIANT 1049 1049 G -> S (in OI3).
FT /FTId=VAR_001708.
FT VARIANT 1052 1052 G -> GAPG (in OI2).
FT /FTId=VAR_063333.
FT VARIANT 1055 1055 G -> D (in OI2).
FT /FTId=VAR_063334.
FT VARIANT 1058 1058 G -> S (in OI3 and OI4; mild form).
FT /FTId=VAR_001709.
FT VARIANT 1061 1061 G -> D (in OI2).
FT /FTId=VAR_001710.
FT VARIANT 1061 1061 G -> S (in OI4).
FT /FTId=VAR_001711.
FT VARIANT 1066 1066 R -> C (in a patient with overlapping
FT features of osteogenesis imperfecta and
FT Ehlers-Danlos syndrome; pathogenic
FT mutation; affects dimer formation, helix
FT stability and organization of collagen
FT fibrils).
FT /FTId=VAR_063335.
FT VARIANT 1075 1075 T -> A (in dbSNP:rs1800215).
FT /FTId=VAR_001712.
FT VARIANT 1076 1076 G -> S (in OI3; severe form).
FT /FTId=VAR_001713.
FT VARIANT 1079 1079 G -> S (in OI1 and OI2; mild to moderate
FT form).
FT /FTId=VAR_001714.
FT VARIANT 1082 1082 G -> C (in OI2).
FT /FTId=VAR_001715.
FT VARIANT 1088 1088 G -> A (in OI2).
FT /FTId=VAR_001716.
FT VARIANT 1091 1091 G -> S (in OI2).
FT /FTId=VAR_001717.
FT VARIANT 1093 1093 R -> C (in a patient with isolated
FT osteopenia and vascular rupture).
FT /FTId=VAR_063336.
FT VARIANT 1094 1094 G -> S (in OI2).
FT /FTId=VAR_063337.
FT VARIANT 1100 1100 G -> D (in OI2).
FT /FTId=VAR_001718.
FT VARIANT 1106 1106 G -> A (in OI2).
FT /FTId=VAR_001719.
FT VARIANT 1124 1124 G -> C (in OI2).
FT /FTId=VAR_001720.
FT VARIANT 1141 1141 R -> Q (in dbSNP:rs41316713).
FT /FTId=VAR_033778.
FT VARIANT 1142 1142 G -> S (in OI2).
FT /FTId=VAR_001721.
FT VARIANT 1151 1151 G -> S (in OI3).
FT /FTId=VAR_001722.
FT VARIANT 1151 1151 G -> V (in OI2).
FT /FTId=VAR_001723.
FT VARIANT 1154 1154 G -> R (in OI2).
FT /FTId=VAR_001724.
FT VARIANT 1157 1157 G -> D (in OI1).
FT /FTId=VAR_063338.
FT VARIANT 1166 1166 G -> C (in OI2).
FT /FTId=VAR_001725.
FT VARIANT 1172 1172 G -> D (in OI2).
FT /FTId=VAR_001726.
FT VARIANT 1177 1177 V -> I (in dbSNP:rs41316719).
FT /FTId=VAR_033779.
FT VARIANT 1181 1181 G -> S (in OI2).
FT /FTId=VAR_001727.
FT VARIANT 1184 1184 G -> V (in OI2).
FT /FTId=VAR_001728.
FT VARIANT 1187 1187 G -> S (in OI2 and OI3; extremely severe
FT form).
FT /FTId=VAR_001729.
FT VARIANT 1187 1187 G -> V (in OI2).
FT /FTId=VAR_001730.
FT VARIANT 1195 1195 G -> C (in OI1; mild form).
FT /FTId=VAR_001731.
FT VARIANT 1219 1219 D -> E (in OI1).
FT /FTId=VAR_063339.
FT VARIANT 1219 1219 D -> N (in a patient with mild
FT osteogenesis imperfecta associated with
FT increased bone mineral density; results
FT in defective type I procollagen
FT processing; incorporation of the immature
FT procollagen into the matrix leads to
FT increased bone matrix mineralization and
FT altered collagen fibril structure).
FT /FTId=VAR_066385.
FT VARIANT 1251 1251 S -> T (in dbSNP:rs3205325).
FT /FTId=VAR_030014.
FT VARIANT 1277 1277 D -> H (in OI2; impaired pro-alpha chain
FT association).
FT /FTId=VAR_001732.
FT VARIANT 1312 1312 W -> C (in OI2).
FT /FTId=VAR_001733.
FT VARIANT 1337 1338 Missing (in OI2; impaired pro-alpha chain
FT association).
FT /FTId=VAR_001734.
FT VARIANT 1356 1356 R -> H.
FT /FTId=VAR_063340.
FT VARIANT 1388 1388 L -> R (in OI2; impaired pro-alpha chain
FT association).
FT /FTId=VAR_001735.
FT VARIANT 1391 1391 Q -> K (in dbSNP:rs2586486).
FT /FTId=VAR_030015.
FT VARIANT 1413 1413 D -> N (in OI2).
FT /FTId=VAR_063341.
FT VARIANT 1430 1430 K -> N (in dbSNP:rs1059454).
FT /FTId=VAR_033780.
FT VARIANT 1431 1431 T -> P (in dbSNP:rs1059454).
FT /FTId=VAR_033781.
FT VARIANT 1434 1434 T -> S (in dbSNP:rs1800220).
FT /FTId=VAR_001736.
FT VARIANT 1438 1438 P -> R (in dbSNP:rs17857117).
FT /FTId=VAR_030016.
FT VARIANT 1460 1460 P -> H (in dbSNP:rs17853657).
FT /FTId=VAR_030017.
FT VARIANT 1464 1464 L -> P (in OI3).
FT /FTId=VAR_001737.
FT CONFLICT 59 59 R -> Q (in Ref. 8; CAA25394).
FT CONFLICT 112 114 Missing (in Ref. 2; AAB94054).
FT CONFLICT 288 288 E -> P (in Ref. 15; AA sequence).
FT CONFLICT 370 370 R -> L (in Ref. 6; AAB59373).
FT CONFLICT 484 484 P -> L (in Ref. 19; AAA52289).
FT CONFLICT 595 595 A -> R (in Ref. 20; AAA51847).
FT CONFLICT 721 721 Q -> E (in Ref. 22; no nucleotide entry).
FT CONFLICT 738 738 L -> E (in Ref. 22; no nucleotide entry).
FT CONFLICT 975 976 LP -> PL (in Ref. 19; AAA52291).
FT CONFLICT 1081 1081 V -> A (in Ref. 18; AAA51995).
FT CONFLICT 1329 1329 S -> T (in Ref. 25; AAB27856).
FT STRAND 264 266
FT STRAND 966 968
SQ SEQUENCE 1464 AA; 138941 MW; F0EC4DE778FFFC11 CRC64;
MFSFVDLRLL LLLAATALLT HGQEEGQVEG QDEDIPPITC VQNGLRYHDR DVWKPEPCRI
CVCDNGKVLC DDVICDETKN CPGAEVPEGE CCPVCPDGSE SPTDQETTGV EGPKGDTGPR
GPRGPAGPPG RDGIPGQPGL PGPPGPPGPP GPPGLGGNFA PQLSYGYDEK STGGISVPGP
MGPSGPRGLP GPPGAPGPQG FQGPPGEPGE PGASGPMGPR GPPGPPGKNG DDGEAGKPGR
PGERGPPGPQ GARGLPGTAG LPGMKGHRGF SGLDGAKGDA GPAGPKGEPG SPGENGAPGQ
MGPRGLPGER GRPGAPGPAG ARGNDGATGA AGPPGPTGPA GPPGFPGAVG AKGEAGPQGP
RGSEGPQGVR GEPGPPGPAG AAGPAGNPGA DGQPGAKGAN GAPGIAGAPG FPGARGPSGP
QGPGGPPGPK GNSGEPGAPG SKGDTGAKGE PGPVGVQGPP GPAGEEGKRG ARGEPGPTGL
PGPPGERGGP GSRGFPGADG VAGPKGPAGE RGSPGPAGPK GSPGEAGRPG EAGLPGAKGL
TGSPGSPGPD GKTGPPGPAG QDGRPGPPGP PGARGQAGVM GFPGPKGAAG EPGKAGERGV
PGPPGAVGPA GKDGEAGAQG PPGPAGPAGE RGEQGPAGSP GFQGLPGPAG PPGEAGKPGE
QGVPGDLGAP GPSGARGERG FPGERGVQGP PGPAGPRGAN GAPGNDGAKG DAGAPGAPGS
QGAPGLQGMP GERGAAGLPG PKGDRGDAGP KGADGSPGKD GVRGLTGPIG PPGPAGAPGD
KGESGPSGPA GPTGARGAPG DRGEPGPPGP AGFAGPPGAD GQPGAKGEPG DAGAKGDAGP
PGPAGPAGPP GPIGNVGAPG AKGARGSAGP PGATGFPGAA GRVGPPGPSG NAGPPGPPGP
AGKEGGKGPR GETGPAGRPG EVGPPGPPGP AGEKGSPGAD GPAGAPGTPG PQGIAGQRGV
VGLPGQRGER GFPGLPGPSG EPGKQGPSGA SGERGPPGPM GPPGLAGPPG ESGREGAPGA
EGSPGRDGSP GAKGDRGETG PAGPPGAPGA PGAPGPVGPA GKSGDRGETG PAGPTGPVGP
VGARGPAGPQ GPRGDKGETG EQGDRGIKGH RGFSGLQGPP GPPGSPGEQG PSGASGPAGP
RGPPGSAGAP GKDGLNGLPG PIGPPGPRGR TGDAGPVGPP GPPGPPGPPG PPSAGFDFSF
LPQPPQEKAH DGGRYYRADD ANVVRDRDLE VDTTLKSLSQ QIENIRSPEG SRKNPARTCR
DLKMCHSDWK SGEYWIDPNQ GCNLDAIKVF CNMETGETCV YPTQPSVAQK NWYISKNPKD
KRHVWFGESM TDGFQFEYGG QGSDPADVAI QLTFLRLMST EASQNITYHC KNSVAYMDQQ
TGNLKKALLL QGSNEIEIRA EGNSRFTYSV TVDGCTSHTG AWGKTVIEYK TTKTSRLPII
DVAPLDVGAP DQEFGFDVGP VCFL
//

MIM 114000
*RECORD*
*FIELD* NO
114000
*FIELD* TI
#114000 CAFFEY DISEASE
;;INFANTILE CORTICAL HYPEROSTOSIS
PRENATAL CORTICAL HYPEROSTOSIS, LETHAL, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
Caffey disease is caused by heterozygous mutation in the alpha-1
collagen type I gene (COL1A1; 120150) on chromosome 17q21.

CLINICAL FEATURES

Infantile cortical hyperostosis has somewhat unusual features for a
hereditary disorder. It rarely if ever appears after 5 months of age and
usually resolves spontaneously by 2 years of age; it is sometimes
present at birth and has been identified by x-ray in the fetus in utero.
The acute manifestations are inflammatory in nature, with fever and hot,
tender swelling of involved bones (e.g., mandible, ribs). Despite
striking radiologic changes in the acute stages, previously affected
bones are often completely normal on restudy. However, Taj-Eldin and
Al-Jawad (1971) described a case followed since infancy with recurrences
documented up to 19 years of age (1971). (Incontinentia pigmenti
(308300) is another familial condition in which 'active' lesions at
birth and early in life may leave little or no residue.) Pickering and
Cuddigan (1969) suggested that vascular occlusion secondary to
thrombocytosis may be involved in the pathogenesis. X-ray findings in 3
members of the family were reported by Pajewski and Vure (1967).

MacLachlan et al. (1984) followed up on the French-Canadian kindred
reported by Gerrard et al. (1961). To the 14 affected children
identified in the original report, 20 new cases were added. MacLachlan
et al. (1984) commented that the sporadic form of the disorder is
disappearing with no such cases seen in the last 7 years. In sporadic
cases the bones most often affected are mandible, ulna, and clavicle
with fairly frequent involvement of ribs and scapulae. In their
radiographic studies of 14 familial cases, no involvement of ribs or
scapulae was encountered. Clavicular involvement was found in only 3
children. The tibia was most often involved in familial cases.
Borochowitz et al. (1991) described 2 affected sibs in a
nonconsanguineous family; a girl had involvement of the fibula at the
age of 5 months and a recurrence with tibial involvement at the age of
11 years. Her brother was hospitalized at the age of 4 months because of
swelling of the face, fever, and restlessness.

Suphapeetiporn et al. (2007) reported a 3-generation Thai family in
which 5 individuals had Caffey disease. The oldest individual, a
75-year-old man, had bowed legs since childhood, several traumatic
fractures, short hands, kyphoscoliosis and compression fractures of the
vertebrae. Examination of other affected family members showed angular
deformities of the long bones, short stature, and dental caries,
although unaffected family members also had dental caries. The authors
suggested that short stature and persistent bony deformities should be
included in the clinical spectrum of Caffey disease.

- Prenatal Cortical Hyperostosis, Lethal

Lecolier et al. (1992) described a case of prenatal Caffey disease.
Ultrasound examination at 20 weeks' gestation detected major angulation
of the long bones. Although no fractures were seen, irregularities of
the ribs suggested multiple callus formation and the diagnosis of lethal
osteogenesis imperfecta was entertained. Cordocentesis showed marked
leukocytosis, mainly due to neutrophils, as well as increased serum
levels of hepatic enzymes. Because of a rapid appearance of
'fetoplacental anasarca' and a probable diagnosis of osteogenesis
imperfecta, pregnancy was terminated at 23 weeks' gestation. Special
x-ray views showed a double contour of the diaphyseal cortex of the long
bones. Histologic examination confirmed the diagnosis of Caffey disease
by demonstration of thickened periosteum and infiltration of the deeper
layers of the periosteum with round cells. Lecolier et al. (1992)
suggested that this form should be referred to as lethal prenatal
cortical hyperostosis.

Perinatal death in 2 sibs with Caffey disease was described by de Jong
and Muller (1995). Antenatal sonographic diagnosis was short-limb
dwarfism and thoracic dysplasia of a nonspecific type, possibly
osteogenesis imperfecta, in the first sib. The second sib had a similar
appearance on ultrasonography. The thickened irregularly echodense
diaphyses were an aid to diagnosis. De Jong and Muller (1995) agreed
with LeColier et al. (1992) that fetoplacental anasarca and
polyhydramnios are helpful prognostic signs. The presence of both seems
to indicate a very poor prognosis. Autosomal dominant inheritance with
subclinical Caffey disease in one of the parents during infancy could
not be excluded since incidental discovery of the disease has been
reported (Cayler and Peterson, 1956). Parental gonadal mosaicism is
another possibility. In spite of the absence of parental consanguinity,
the occurrence of the condition in a male and a female sib born to
healthy parents suggested autosomal recessive inheritance of the lethal
prenatal onset type of cortical hyperostosis.

Kamoun-Goldrat et al. (2008) described a fetus that represented the
first pregnancy of a young, healthy, nonconsanguineous couple. The
pregnancy was medically terminated at 30 weeks' gestation after a
diagnosis of severe osteogenesis imperfecta. Postmortem radiographs,
autopsy, and histologic study showed typical features of a severe form
of prenatal cortical hyperostosis.

DIAGNOSIS

- Prenatal Diagnosis

Stevenson (1993) described a case indicating that Caffey disease can be
detected in utero in familial nonlethal cases. Ultrasound examination at
age 35.5 weeks showed curvature of the tibia and irregularity of the
cortex of the radius. Mild leg curvature was present at birth at 39
weeks; involvement of all long bones was documented radiographically at
the age of 2.5 months. A sister, the mother, and a maternal uncle had
documented Caffey disease.

INHERITANCE

Autosomal dominant inheritance of Caffey disease is suggested by the
reports of Gerrard et al. (1961), Van Buskirk et al. (1961), Holman
(1962), and others. Male-to-male transmission was observed by Van
Buskirk et al. (1961). Bull and Feingold (1974) reported 2 affected
sisters, one of whom had affected son and daughter and the other a
normal daughter and affected son. Fried et al. (1981) observed 9
affected persons in 3 sibships of 2 generations of a family. One
instance of male-to-male transmission and one of apparent nonpenetrance
were reported. Newberg and Tampas (1981) gave a follow-up on a family
with 11 cases reported in 1961 (Tampas et al., 1961; Van Buskirk et al.,
1961). Since then, 10 new cases had occurred, confirming autosomal
dominant inheritance. Emmery et al. (1983) described 8 affected persons
in 3 generations.

Of the 24 affected members of a family segregating Caffey disease in
which Gensure et al. (2005) identified an R836C mutation in the COL1A1
gene (120150.0063), only 19 (79%) had experienced an episode of cortical
hyperostosis and 5 (21%) obligate carriers had not, consistent with
reduced penetrance.

MAPPING

Gensure et al. (2005) performed genomewide mapping of a large family
with Caffey disease, which revealed linkage to chromosome 17q21. Fine
mapping reduced the linked region to a 2.3-Mb interval between markers
D17S1868 and D17S1877; the maximum 2-point lod score obtained was 6.78
for marker D17S1795 (theta = 0.0).

MOLECULAR GENETICS

In affected individuals and obligate carriers from 3 unrelated families
with Caffey disease, Gensure et al. (2005) identified heterozygosity for
an arg836-to-cys mutation in the COL1A1 gene (R836C; 120150.0063),
involving the triple-helical domain of the alpha-1 chain of type I
collagen. None of the affected individuals or obligate carriers in any
of the families had clinical signs of the major type I collagen
disorder, osteogenesis imperfecta (see 166200); however, in 2 of the 3
families, individuals carrying the mutation did have joint hyperlaxity,
hyperextensible skin, and inguinal hernias, features seen in
Ehlers-Danlos syndrome (see 130000), some forms of which are caused by
mutations in COL1A1.

In affected members of a Thai family with Caffey disease, Suphapeetiporn
et al. (2007) identified heterozygosity for the R836C mutation in the
COL1A1 gene.

Kamoun-Goldrat et al. (2008) identified heterozygosity for the R836C
mutation in the COL1A1 gene in the pulmonary tissue of a fetus with a
severe form of prenatal cortical hyperostosis from a terminated
pregnancy at 30 weeks' gestation. They noted that this mutation had not
been found in 2 other such cases by Gensure et al. (2005) and speculated
that mutations in other genes were likely involved in the prenatal and
infantile forms of cortical hyperostosis.

HISTORY

See Griscom (1995) for a biographic account of John Caffey (1895-1978).

*FIELD* SA
Caffey and Silverman (1945); Clemett and Williams (1963); Langewisch
(1975); Sherman and Hellyer (1950); Sidbury (1957)
*FIELD* RF
1. Borochowitz, Z.; Gozal, D.; Misselevitch, I.; Aunallah, J.; Boss,
J. H.: Familial Caffey's disease and late recurrence in a child. Clin.
Genet. 40: 329-335, 1991.

2. Bull, M. J.; Feingold, M.: Autosomal dominant inheritance of Caffey
disease. Birth Defects Orig. Art. Ser. X: 139-146, 1974.

3. Caffey, J.; Silverman, W.: Infantile cortical hyperostosis, preliminary
report on new syndrome. Am. J. Roentgen. 54: 1-16, 1945.

4. Cayler, G. G.; Peterson, C. A.: Infantile cortical hyperostosis:
report of seventeen cases. Am. J. Dis. Child. 91: 119-125, 1956.

5. Clemett, A. R.; Williams, J. H.: The familial occurrence of infantile
cortical hyperostosis. Radiology 80: 409-416, 1963.

6. de Jong, G.; Muller, L. M. M.: Perinatal death in two sibs with
infantile cortical hyperostosis (Caffey disease). Am. J. Med. Genet. 59:
134-138, 1995.

7. Emmery, L.; Timmermans, J.; Christens, J.; Fryns, J. P.: Familial
infantile cortical hyperostosis. Europ. J. Pediat. 141: 56-58, 1983.

8. Fried, K.; Manor, A.; Pajewski, M.; Starinsky, R.; Vure, E.: Autosomal
dominant inheritance with incomplete penetrance of Caffey disease
(infantile cortical hyperostosis). Clin. Genet. 19: 271-274, 1981.

9. Gensure, R. C.; Makitie, O.; Barclay, C.; Chan, C.; DePalma, S.
R.; Bastepe, M.; Abuzahra, H.; Couper, R.; Mundlos, S.; Sillence,
D.; Ala Kokko, L.; Seidman, J. G.; Cole, W. G.; Juppner, H.: A novel
COL1A1 mutation in infantile cortical hyperostosis (Caffey disease)
expands the spectrum of collagen-related disorders. J. Clin. Invest. 115:
1250-1257, 2005.

10. Gerrard, J. W.; Holman, G. H.; Gorman, A. A.; Morrow, I. H.:
Familial infantile cortical hyperostosis. J. Pediat. 59: 543-548,
1961.

11. Griscom, N. T.: John Caffey and his contributions to radiology. Radiology 194:
513-518, 1995.

12. Holman, G. H.: Infantile cortical hyperostosis: a review. Quart.
Rev. Pediat. 17: 24-31, 1962.

13. Kamoun-Goldrat, A.; Martinovic, J.; Saada, J.; Sonigo-Cohen, P.;
Razavi, F.; Munnich, A.; Le Merrer, M.: Prenatal cortical hyperostosis
with COL1A1 gene mutation. Am. J. Med. Genet. 146A: 1820-1824, 2008.

14. Langewisch, W. H.: Infantile cortical hyperostosis--familial
occurrence in a mother and daughter. J. Pediat. 87: 323-324, 1975.

15. Lecolier, B.; Bercau, G.; Gonzales, M.; Afriat, R.; Rambaud, D.;
Mulliez, N.; de Kermadec, S.: Radiographic, haematological, and biochemical
findings in a fetus with Caffey disease. Prenatal Diag. 12: 637-641,
1992.

16. MacLachlan, A. K.; Gerrard, J. W.; Houston, C. S.; Ives, E. J.
: Familial infantile cortical hyperostosis in a large Canadian family. Canad.
Med. Assoc. J. 130: 1172-1174, 1984.

17. Newberg, A. H.; Tampas, J. P.: Familial infantile cortical hyperostosis:
an update. Am. J. Roentgen. 137: 93-96, 1981.

18. Pajewski, M.; Vure, E.: Late manifestations of infantile cortical
hyperostosis (Caffey's disease). Brit. J. Radiol. 40: 90-95, 1967.

19. Pickering, D.; Cuddigan, B.: Infantile cortical hyperostosis
associated with thrombocythaemia. Lancet 294: 464-465, 1969. Note:
Originally Volume II.

20. Sherman, M. S.; Hellyer, D. T.: Infantile cortical hyperostosis:
review of the literature and report of 5 cases. Am. J. Roentgen. 63:
212-222, 1950.

21. Sidbury, J. B., Jr.: Infantile cortical hyperostosis. Postgrad.
Med. J. 22: 211-215, 1957.

22. Stevenson, R. E.: Findings of heritable Caffey disease on ultrasound
at 35 1/2 weeks gestation. Proc. Greenwood Genet. Center 12: 16-18,
1993.

23. Suphapeetiporn, K.; Tongkobpetch, S.; Mahayosnond, A.; Shotelersuk,
V.: Expanding the phenotypic spectrum of Caffey disease. Clin. Genet. 71:
280-284, 2007.

24. Taj-Eldin, S.; Al-Jawad, J.: Cortical hyperostosis: infantile
and juvenile manifestations in a boy. Arch. Dis. Child. 46: 565-566,
1971.

25. Tampas, J. P.; Van Buskirk, F. W.; Peterson, O. S.; Soule, A.
B.: Infantile cortical hyperostosis. JAMA 175: 491-493, 1961.

26. Van Buskirk, F. W.; Tampas, J. P.; Peterson, O. S.: Infantile
cortical hyperostosis: an inquiry into its familial aspects. Am.
J. Roentgen. 85: 613-632, 1961.

*FIELD* CS

Skel:
Hot, tender swelling of involved bones (e.g., mandible, ribs)

Limbs:
Mild congenital leg curvature

Misc:
Usually appears by 5 months of age;
Fever;
Specific bones involved different in familial and sporadic cases

Radiology:
Identified by x-ray in the fetus in utero;
Cortical hyperostosis;
Curved tibia;
Irregularity of bone cortex

Lab:
Thickened periosteum and infiltration of the deeper layers of the
periosteum with round cells

Inheritance:
Autosomal dominant

*FIELD* CN
Nara Sobreira - updated: 6/17/2009
Cassandra L. Kniffin - updated: 8/29/2007
Marla J. F. O'Neill - updated: 5/20/2005

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 04/05/2012
carol: 6/18/2009
terry: 6/17/2009
terry: 6/3/2009
terry: 1/8/2009
wwang: 9/10/2007
ckniffin: 8/29/2007
carol: 6/23/2005
carol: 5/25/2005
wwang: 5/23/2005
terry: 5/20/2005
alopez: 3/17/2004
alopez: 4/8/1999
alopez: 7/9/1997
terry: 3/26/1996
mark: 1/16/1996
terry: 1/11/1996
carol: 3/7/1995
davew: 6/9/1994
terry: 5/13/1994
mimadm: 4/9/1994
warfield: 4/6/1994
carol: 10/26/1993

MIM 120150
*RECORD*
*FIELD* NO
120150
*FIELD* TI
+120150 COLLAGEN, TYPE I, ALPHA-1; COL1A1
;;COLLAGEN OF SKIN, TENDON, AND BONE, ALPHA-1 CHAIN
read moreCOL1A1/PDGFB FUSION GENE, INCLUDED;;
OI/EDS COMBINED SYNDROME, INCLUDED
*FIELD* TX

DESCRIPTION

Collagen has a triple-stranded rope-like coiled structure. The major
collagen of skin, tendon, and bone is the same protein containing 2
alpha-1 polypeptide chains and 1 alpha-2 chain. Although these are long
(the procollagen chain has a molecular mass of about 120 kD, before the
'registration peptide' is cleaved off; see 225410), each messenger RNA
is monocistronic (Lazarides and Lukens, 1971). Differences in the
collagens from these 3 tissues are a function of the degree of
hydroxylation of proline and lysine residues, aldehyde formation for
cross-linking, and glycosylation. The alpha-1 chain of the collagen of
cartilage and that of the collagen of basement membrane are determined
by different structural genes. The collagen of cartilage contains only 1
type of polypeptide chain, alpha-1, and this is determined by a distinct
locus. The fetus contains collagen of distinctive structure. The genes
for types I, II, and III collagens, the interstitial collagens, exhibit
an unusual and characteristic structure of a large number of relatively
small exons (54 and 108 bp) at evolutionarily conserved positions along
the length of the triple helical gly-X-Y portion (Boedtker et al.,
1983). The family of collagen proteins consists of a minimum of 9 types
of collagen molecules whose constituent chains are encoded by a minimum
of 17 genes (Ninomiya and Olsen, 1984).

CLONING

Tromp et al. (1988) characterized a full-length cDNA clone for the
COL1A1 gene.

MAPPING

Sundar Raj et al. (1977) used the methods of cell hybridization and
microcell hybridization to assign a collagen I gene to chromosome 17.
Solomon and Sykes (1979) concluded, incorrectly as it turned out, that
both the alpha-1 and the alpha-2 genes of collagen I are on chromosome
7. Solomon and Sykes (1979) also presented evidence that the alpha-1
chains of collagen III are also coded by chromosome 7. Church et al.
(1981) assigned a structural gene for corneal type I procollagen to
chromosome 7 by somatic cell hybridization involving corneal stromal
fibroblasts. Because they had previously assigned a gene for skin type I
procollagen to chromosome 17, they wondered whether skin and corneal
type I collagen may be under separate control.

Huerre et al. (1982) used a cDNA probe in both mouse-man and Chinese
hamster-man somatic cell hybrids to demonstrate cosegregation with human
chromosome 17. In situ hybridization using the same probe indicated that
the gene is in the middle third of the long arm, probably in band 17q21
or 17q22.

By chromosome-mediated gene transfer (CMGT), Klobutcher and Ruddle
(1979) transferred the genes for thymidine kinase, galactokinase
(604313), and type I procollagen (gene for alpha-1 polypeptide). The
data indicated the following gene order: centromere--GALK--(TK1-COL1A1).
Later studies (Ruddle, 1982) put the growth hormone gene cluster (see
139250) between GALK and (TK1-COL1A1).

A HindIII restriction site polymorphism in the alpha-1(I) gene was
described by Driesel et al. (1982), who probably unjustifiably stated
that the gene is on chromosome 7. By in situ hybridization, Retief et
al. (1985) concluded that the alpha-1(I) and alpha-2(I) genes are
located in bands 17q21.31-q22.05 and 7q21.3-q22.1, respectively.

Sippola-Thiele et al. (1986) commented on the limited number of
informative RFLPs in the collagen genes, especially COL1A1. They
proposed a method for assessing RFLPs that were otherwise undetectable
in total human genomic DNA. Using the centromere-based locus D17Z1,
Tsipouras et al. (1988) found a recombination fraction of 0.20 with
COL1A1. Furthermore, they demonstrated that COL1A1 and GH1 (139250) show
a recombination fraction of 0.10. They proposed that the most likely
order is D17Z1--COL1A1--GH1.

Byrne and Church (1983) had concluded that both subunits of type I
collagen, alpha-1 and alpha-2, are coded by chromosome 16 in the mouse.
SOD1 (147450), which in man is on chromosome 21, is also carried by
mouse 16. It may have been type VI collagen (120220, 120240) that they
dealt with; both COL6A1 and COL6A2 are coded by human chromosome 21. (In
fact, the Col6a1 and Col6a2 genes are carried by mouse chromosome 10
(Justice et al., 1990).) Munke et al. (1986) showed that the alpha-1
gene of type I collagen is located on mouse chromosome 11; the Moloney
murine leukemia virus is stably integrated into this site when
microinjected into the pronuclei of fertilized eggs. This insertion
results in a lethal mutation through blockage of the developmentally
regulated expression of the gene (Schnieke et al., 1983).

MOLECULAR GENETICS

- Osteogenesis Imperfecta

Pope et al. (1985) described a substitution of cysteine in the
C-terminal end of the alpha-1 collagen chain in a 9-year-old boy with
mild osteogenesis imperfecta (OI) of Sillence type I. They assumed that
this was a substitution for either arginine or serine (which could be
accomplished by a single base change) because substitution of cysteine
for glycine produced a much more drastic clinical picture. In a neonatal
lethal case of OI congenita, Barsh and Byers (1981) demonstrated a
defect in pro-alpha-1 chains (see OI type II, 166210).

Byers et al. (1988) found an insertion in one COL1A1 allele in an infant
with OI II. One alpha-1 chain was normal in length, whereas the other
contained an insertion of approximately 50-70 amino acid residues within
the triple helical domain defined by amino acids 123-220. The structure
of the insertion was consistent with duplication of an approximately
600-bp segment in 1 allele.

Brookes et al. (1989) used an S1 nuclease directed cleavage of
heteroduplex DNA molecules formed between genomic material and cloned
sequences to search for mutations in the COL1A1 gene in 5 cases in which
previous linkage studies had shown the mutation to be located in the
COL1A1 gene and in 4 cases in which a COL1A1 null allele had been
identified by protein and RNA studies. No abnormality was found in the
complete 18 kb COL1A1 gene or in 2 kb of 5-prime flanking sequence. The
method used was known to permit the detection of short length variations
of the order of 4 bp in heterozygous subjects but not single basepair
alterations. Thus, Brookes et al. (1989) suggested that single basepair
alterations may be the predominant category of mutation in type I OI.

COL1A1 and NGFR (162010) are in the same restriction fragment. In a
3-generation family with OI type I, Willing et al. (1990) found that all
affected members had one normal COL1A1 allele and another from which the
intragenic EcoRI restriction site near the 3-prime end of the gene was
missing. They found, furthermore, a 5-bp deletion at the EcoRI site
which changed the translational reading frame and predicted the
synthesis of a pro-alpha-1(I) chain that extended 84 amino acids beyond
the normal termination. Although the mutant chain was synthesized in an
in vitro translation system, they were unable to detect its presence in
intact cells, suggesting that it is unstable and rapidly destroyed in
one of the cell's degradative pathways.

Cohn et al. (1990) demonstrated a clear instance of paternal germline
mosaicism as the cause of 2 offspring with OI type I by different women.
Both affected infants had a G-to-A change that resulted in substitution
of aspartic acid for glycine at position 883 of the alpha-1 chain of
type I collagen. Although not detected in the father's skin fibroblasts,
the mutation was detected in somatic DNA from the father's hair root
bulbs and lymphocytes. It was also found in the father's sperm where
about 1 in 8 sperm carried the mutation, suggesting that at least 4
progenitor cells populate the germline in human males. The father was
clinically normal. In an infant with perinatal lethal OI (OI type II),
Wallis et al. (1990) demonstrated both normal and abnormal type I
procollagen molecules. The abnormal molecules had substitution of
arginine for glycine at position 550 of the triple-helical domain as a
result of a G-to-A transition in the first base of the glycine codon.
The father was shown to be mosaic for this mutation, which accounted for
about 50% of the COL1A1 alleles in his fibroblasts, 27% of those in
blood cells, and 37% of those in sperm. The father was short of stature;
he had bluish sclerae, grayish discoloration of the teeth (which were
small), short neck, barrel-shaped chest, right inguinal hernia, and
hyperextensible fingers and toes. A triangular-shaped head had been
noted at birth and he was thought to have hydrocephalus. No broken bones
had been noted at that time. He had had only 1 fracture, that of the
clavicle at age 8 years.

Cole et al. (1990) reported the clinical features of 3 neonates with
lethal perinatal OI resulting from a substitution of glycine by arginine
in the COL1A1 gene product. The mutations were gly391-to-arg,
gly667-to-arg, and gly976-to-arg. All 3 were small, term babies who died
soon after birth. The ribs were broad and continuously beaded in the
first, discontinuously beaded in the second, and slender with few
fractures in the third. The overall radiographic classifications were
type IIA, IIA/IIB, and IIB, respectively (based on an old classification
by Sillence et al., 1984; see HISTORY in 166210). The findings suggested
that there was a gradient of bone modeling capacity from the slender and
overmodeled bones associated with the mutation nearest the C-terminal
end of the molecule to absence of modeling with that nearest the
N-terminal end.

Dermal fibroblasts from most persons with OI type I produce about half
the normal amount of type I procollagen as a result of decreased
synthesis of one of its constituent chains, namely, the alpha-1 chain.
Willing et al. (1992) used a polymorphic MnlI restriction endonuclease
site in the 3-prime untranslated region of COL1A1 to distinguish the
transcripts of the 2 alleles in 23 heterozygotes from 21 unrelated
families with OI type I. In each case there was marked diminution in
steady-state mRNA levels from one COL1A1 allele. They demonstrated that
loss of an allele through deletion or rearrangement was not the cause of
the diminished COL1A1 mRNA levels. Primer extension with
nucleotide-specific chain termination allowed identification of the
mutant allele in cell strains that were heterozygous for an expressed
polymorphism. Willing et al. (1992) suggested that the method is
applicable to sporadic cases, to small families, and to large families
in which key persons are uninformative at the polymorphic sites used in
linkage analysis.

Willing et al. (1993) pointed out that the abnormally low ratio of
COL1A1 mRNA to COL1A2 (120160) mRNA in fibroblasts cultured from OI type
I patients is an indication of a defect in the COL1A1 gene in the great
majority of patients with this form of OI.

Byers (1993) counted a total of approximately 70 point mutations
identified in the helical portion of the alpha-1 peptide, approximately
10 exon skipping mutations, and about 6 point mutations in the
C-propeptide.

Steady state amounts of COL1A1 mRNA are reduced in both the nucleus and
cytoplasm of dermal fibroblasts from most subjects with type I
osteogenesis imperfecta (166200). Willing et al. (1995) investigated
whether mutations involving key regulatory sequences in the COL1A1
promoter, such as the TATAAA and CCAAAT boxes, are responsible for the
reduced levels of mRNA. They used PCR-amplified genomic DNA in
conjunction with denaturing gradient gel electrophoresis and SSCP to
screen the 5-prime untranslated domain, exon 1, and a small portion of
intron 1 of the COL1A1 gene. In addition, direct sequence analysis was
performed on an amplified genomic DNA fragment that included the TATAAA
and CCAAAT boxes. In a survey of 40 unrelated probands with OI type I in
whom no causative mutation was known, Willing et al. (1995) identified
no mutations in the promoter region and there was 'little evidence of
sequence diversity among any of the 40 subjects.'

Whereas most cases of severe osteogenesis imperfecta result from
mutations in the coding region of the COL1A1 or COL1A2 genes yielding an
abnormal collagen alpha-chain, many patients with mild OI show evidence
of a null allele due to a premature stop mutation in the mutant RNA
transcript. As indicated in 120150.0046, mild OI in one case resulted
from a null allele arising from a splice donor mutation where the
transcript containing the included intron was sequestered in the
nucleus. Nuclear sequestration precluded its translation and thus
rendered the allele null. Using RT-PCR and SSCP of COL1A1 mRNA from
patients with mild OI, Redford-Badwal et al. (1996) identified 3
patients with distinct null-producing mutations identified from the
mutant transcript within the nuclear compartment. In a fourth patient
with a gly-to-arg expressed point mutation, they found the mutant
transcript in both the nucleus and the cytoplasm.

Willing et al. (1996) analyzed the effects of nonsense and frameshift
mutations on steady state levels of COL1A1 mRNA. Total cellular and
nuclear RNA was analyzed. They found that mutations which predict
premature termination reduce steady-state amounts of COL1A1 mRNA from
the mutant allele in both nuclear and cellular mRNA. The investigators
concluded that premature termination mutations have a predictable and
uniform effect on COL1A1 gene expression which ultimately leads to
decreased production of type I collagen and to the mild phenotype
associated with OI type I. Willing et al. (1996) reported that mutations
which lead to premature translation termination appear to be the most
common molecular cause of OI type I. They identified 21 mutations, 15 of
which lead to premature termination as a result of translational
frameshifts or single-nucleotide substitutions. Five mutations were
splicing defects leading to cryptic splicing or intron retention within
the mature mRNA. Both of these alternative splicing pathways indirectly
lead to frameshifts and premature termination in downstream exons.

In 4 apparently unrelated patients with OI, Korkko et al. (1997) found 2
new recurrent nucleotide mutations in the COL1A1 gene, using a protocol
whereby 43 exons and exon-flanking sequences were amplified by PCR and
scanned for mutations by denaturing gradient gel electrophoresis. From
an analysis of previous publications, they concluded that up to
one-fifth of mutations causing OI are recurrent in the sense that they
are identical in apparently unrelated probands. About 80% of these
identical mutations were found to be in CpG dinucleotide sequences.
Korkko et al. (1997) tabulated reported cases of recurrent mutations
causing OI. The most frequent recurrent mutation was gly352ser
(120150.0042), reported in 4 unrelated patients. They also reported a
nonsense mutation in the codon for arginine-963 (120150.0055).

Since collagen I consists of 2 alpha-1 chains and 1 alpha-2 chain, a
mutation in the COL1A1 gene might affect the function of the collagen
molecule more than would a similar substitution in the COL1A2 gene,
thereby causing more severe OI, for example. Lund et al. (1997) tested
this hypothesis by comparing patients with identical substitutions in
different alpha chains. They presented a G586V substitution in the
alpha-1 gene (120150.0056) and compared it with a G586V substitution in
the alpha-2 gene (120160.0023). Their patient had lethal OI type II.
Patients with the same substitution in the alpha-2 chain had either OI
type IV (166220) or type III (259420). Lund et al. (1997) pointed out
that identical biochemical alterations in the same chain are known to
have different phenotypic effects, both within families and between
unrelated patients. They took this into account in their cautious
proposal that substitutions in the alpha-1 chain may have more serious
consequences than similar substitutions in the alpha-2 chain.

Kuivaniemi et al. (1997) summarized the data on 278 different mutations
found in genes for types I, II, III, IX, X, and XI collagens from 317
apparently unrelated patients. Most mutations (217; 78% of the total)
were single-base and either changed the codon of a critical amino acid
(63%) or led to abnormal RNA splicing (13%). Most (155; 56%) of the
amino acid substitutions were those of a bulkier amino acid replacing
the obligatory glycine of the repeating Gly-X-Y sequence of the collagen
triple helix. Altogether, 26 different mutations (9.4%) occurred in more
than 1 unrelated individual. The 65 patients in whom the 26 mutations
were characterized constituted almost one-fifth (20.5%) of the 317
patients analyzed. The mutations in these 6 collagens caused a wide
spectrum of diseases of bone, cartilage, and blood vessels, including
osteogenesis imperfecta, a variety of chondrodysplasias, types IV
(130050) and VII (130060) Ehlers-Danlos syndrome, and, rarely, some
forms of osteoporosis, osteoarthritis, and familiar aneurysms.

(The amino acid numbering system for collagen involves assigning number
1 to the first glycine of the triple helical domain of an alpha chain.
The numbers for the alpha-1 chain of type I collagen can be converted to
positions in the pro-alpha-1 chain by adding 156, and the numbers for
the alpha-2 chain can be converted to the human pro-alpha-2 chain by
adding 68.)

Dalgleish (1997) described a mutation database for the COL1A1 and COL1A2
genes.

Mutations in the COL1A2 gene appear to be very rare causes of type I
osteogenesis imperfecta. Korkko et al. (1998) developed a method for
analysis of the COL1A1 and COL1A2 genes in 15 patients with type I OI
and found only COL1A1 mutations. They described their protocols for PCR
amplification of the exon and exon boundaries of all 103 exons in the
COL1A1 and COL1A2 genes. As previously pointed out, most mutations found
in patients with OI type I introduce either premature termination codons
or aberrant RNA splicing and thereby reduce the expression of the COL1A1
gene. The mutations tend to occur in common sequence context. All 9
mutations, found by Korkko et al. (1998) to convert the arginine codon
CGA to the premature-termination codon TGA, occurred in the sequence
context of G/CCC CGA GG/T of the COL1A1 gene. None was found in 7 CGA
codons for arginine in other sequence contexts of the COL1A1 gene. The
COL1A1 gene has 6 such sequences, whereas the COL1A2 gene has none.

Triple helix formation is a prerequisite for the passage of type I
procollagen from the endoplasmic reticulum and secretion from the cell
to form extracellular fibrils that will support mineral deposition in
bone. In an analysis of cDNA from 11 unrelated individuals with
osteogenesis imperfecta, Pace et al. (2001) found 11 novel, short
in-frame deletions or duplications of 3, 9, or 18 nucleotides in the
helical coding regions of the COL1A1 or COL1A2 collagen genes. Triple
helix formation was impaired, type I collagen alpha chains were
posttranslationally overmodified, and extracellular secretion was
markedly reduced. With one exception, the obligate Gly-Xaa-Yaa repeat
pattern of amino acids in the helical domains was not altered, but the
Xaa and Yaa position residues were out of register relative to the amino
acid sequences of adjacent chains in the triple helix. Thus, the
identity of these amino acids, in addition to third position glycines,
is important for normal helix formation. These findings expanded the
repertoire of uncommon in-frame deletions and duplications in OI, and
provided insight into normal collagen biosynthesis and collagen triple
helix formation.

Cabral et al. (2001) reported a 13-year-old girl with severe type III OI
in whom they identified heterozygosity for a gly76-to-glu substitution
in the COL1A1 gene (120150.0065). The authors stated that this was the
first delineation of a glutamic acid substitution in the alpha-1(I)
chain causing nonlethal osteogenesis imperfecta.

Chamberlain et al. (2004) used adeno-associated virus vectors to disrupt
dominant-negative mutant COL1A1 collagen genes in mesenchymal stem
cells, also known as marrow stromal cells, from individuals with severe
OI, demonstrating successful gene targeting in adult human stem cells.

- Ehlers-Danlos Syndromes

In 2 unrelated patients with classic EDS (130000), Nuytinck et al.
(2000) identified an arg134-to-cys mutation (120150.0059) in the COL1A1
gene.

Cabral et al. (2005) identified 7 children with the combination of
skeletal fragility and characteristics of Ehlers-Danlos syndrome. In
each child they identified a mutation in the first 90 residues of the
helical region of alpha-1(I) collagen. These mutations prevented or
delayed removal of the procollagen N-propeptide by purified N-proteinase
(ADAMTS2; 604539) in vitro and in pericellular assays. The mutant
pN-collagen which resulted was efficiently incorporated into matrix by
cultured fibroblasts and osteoblasts and was prominently present in
newly incorporated and immaturely crosslinked collagen. Dermal collagen
fibrils had significantly reduced cross-sectional diameters,
corroborating incorporation of pN-collagen into fibrils in vivo. The
mutations disrupted disrupted a distinct folding region of high thermal
stability in the first 90 residues at the amino end of type I collagen
and altered the secondary structure of the adjacent N-proteinase
cleavage site. Thus, these mutations are directly responsible for the
bone fragility of OI and indirectly responsible for EDS symptoms, by
interference with N-propeptide removal.

Cabral et al. (2005) hypothesized that the nature of EDS-like symptoms
in OI/EDS patients is similar to type VII EDS (130060) derived primarily
by deletions of the N-propeptide cleavage site in alpha-1(I) and
alpha-2(I) (120160) chains, in EDS VIIA and VIIB, respectively, or by
N-proteinase deficiency in EDS VIIC (225410). It remained unclear why
alpha-1(I)-OI/EDS patients had a somewhat different EDS phenotype (e.g.,
pronounced early scoliosis and no bilateral hip dysplasia) and why their
collagen fibrils had more rounded cross-section under electron
microscopy investigation. Makareeva et al. (2006) demonstrated that 85
N-terminal amino acids of the alpha1(I) chain participate in a highly
stable folding domain, acting as the stabilizing anchor for the amino
end of the type I collagen triple helix. This anchor region is bordered
by a microunfolding region, 15 amino acids in each chain, which includes
no proline or hydroxyproline residues and contains a chymotrypsin
cleavage site. Glycine substitutions and amino acid deletions within the
N-anchor domain induced its reversible unfolding above 34 degrees C. The
overall triple helix denaturation temperature was reduced by 5 to 6
degrees C, similar to complete N-anchor removal. N-propeptide partially
restored the stability of mutant procollagen but not sufficiently to
prevent N-anchor unfolding and a conformational change at the
N-propeptide cleavage site. The ensuing failure of N-proteinase to
cleave at the misfolded site led to incorporation of pN-collagen into
fibrils. As in EDS VIIA/B, fibrils containing pN-collagen are thinner
and weaker causing EDS-like laxity of large and small joints and
paraspinal ligaments. Makareeva et al. (2006) concluded that distinct
structural consequences of N-anchor destabilization result in a distinct
alpha1(I)-OI/EDS phenotype.

- Caffey Disease

In affected individuals and obligate carriers from 3 unrelated families
with Caffey disease (114000), Gensure et al. (2005) identified
heterozygosity for an arg836-to-cys mutation (R836C; 120150.0063) in the
COL1A1 gene. Kamoun-Goldrat et al. (2008) identified heterozygosity for
the R836C mutation in the COL1A1 gene in the pulmonary tissue of a fetus
with a severe form of prenatal cortical hyperostosis (see 114000) from a
terminated pregnancy at 30 weeks' gestation. The authors speculated that
mutation in another gene might also be involved.

- Susceptibility to Osteoporosis

Osteoporosis (166710) is a common disorder with a strong genetic
component. One way in which the genetic component could be expressed is
through polymorphism of COL1A1. Grant et al. (1996) described a novel
G-to-T transversion at the first base of a binding site for the
transcription factor Sp1 (189906) in intron 1 of COL1A1 (dbSNP
rs1800012; 120150.0051). They found that the polymorphism was associated
with low bone density and increased appearance of osteoporotic vertebral
fractures in 299 British women. In a study of 1,778 postmenopausal Dutch
women, Uitterlinden et al. (1998) confirmed the association of the
Sp1-binding site polymorphism and bone mineral density.

Lohmueller et al. (2003) performed a metaanalysis of 301 published
genetic association studies covering 25 different reported associations.
For 8 of the 25 associations, strong evidence of replication of the
initial report was available. One of these 8 was the association between
COL1A1 and osteoporotic fracture as first reported by Grant et al.
(1996). Of a G/T SNP in intron 1, osteoporotic fractures showed
association with the T allele.

In 1,873 Caucasian subjects from 405 nuclear families, Long et al.
(2004) examined the relationship between 3 SNPs in the COL1A1 gene and
bone size at the spine, hip, and wrist. They found suggestive evidence
for an association with wrist size at SNP2 (p = 0.011): after adjusting
for age, sex, height, and weight, subjects with the T allele of SNP2
had, on average, a 3.05% smaller wrist size than noncarriers. Long et
al. (2004) concluded that the COL1A1 gene may have some effect on bone
size variation at the wrist, but not at the spine or hip, in these
families.

Jin et al. (2009) showed that the previously reported 5-prime
untranslated region (UTR) SNPs in the COL1A1 gene (-1997G-T, dbSNP
rs1107946, 120150.0067; -1663indelT, dbSNP rs2412298, 120150.0068;
+1245G-T, dbSNP rs1800012) affected COL1A1 transcription. Transcription
was 2-fold higher with the osteoporosis-associated G-del-T haplotype
compared with the common G-ins-G haplotype. The region surrounding dbSNP
rs2412298 recognized a complex of proteins essential for osteoblast
differentiation and function including NMP4 (ZNF384; 609951) and Osterix
(SP7; 606633), and the osteoporosis-associated -1663delT allele had
increased binding affinity for this complex. Further studies showed that
haplotype G-del-T had higher binding affinity for RNA polymerase II,
consistent with increased transcription of the G-del-T allele, and there
was a significant inverse association between carriage of G-del-T and
bone mineral density (BMD) in a cohort of 3,270 Caucasian women. Jin et
al. (2009) concluded that common polymorphic variants in the 5-prime UTR
of COL1A1 regulate transcription by affecting DNA-protein interactions,
and that increased levels of transcription correlated with reduced BMD
values in vivo by altering the normal 2:1 ratio between alpha-1(I) and
alpha-2(I) chains.

GENOTYPE/PHENOTYPE CORRELATIONS

Di Lullo et al. (2002) stated that binding sites on type I collagen had
been elucidated for approximately half of the almost 50 molecules that
had been found to interact with it. In addition, more than 300 mutations
in type I collagen associated with human connective tissue disorders had
been described. However, the spatial relationships between the
ligand-binding sites and mutation positions had not been examined. Di
Lullo et al. (2002) therefore created a map of type I collagen that
included all of its ligand-binding sites and mutations. The map revealed
several hotspots for ligand interactions on type I collagen and showed
that most of the binding sites locate to its C-terminal half. Moreover,
some potentially relevant relationships between binding sites were
observed on the collagen fibril, including the following: fibronectin-
and certain integrin-binding regions are near neighbors, which may
mechanistically relate to fibronectin-dependent cell-collagen
attachment; proteoglycan binding may influence collagen fibrillogenesis,
cell-collagen attachment, and collagen glycation seen in diabetes and
aging; and mutations associated with osteogenesis imperfecta and other
disorders show apparently nonrandom distribution patterns within both
the monomer and fibril, implying that mutation positions correlate with
disease phenotype.

A missense mutation leading to the replacement of 1 Gly in the
(Gly-Xaa-Yaa)n repeat of the collagen triple helix can cause a range of
heritable connective tissue disorders that depend on the gene in which
the mutation occurs. Persikov et al. (2004) found that the spectrum of
amino acids replacing Gly was not significantly different from that
expected for the COL7A1 (120120)-encoded collagen chains, suggesting
that any Gly replacement will cause dystrophic epidermolysis bullosa
(604129). On the other hand, the distribution of residues replacing Gly
was significantly different from that expected for all other collagen
chains studied, with a particularly strong bias seen for the collagen
chains encoded by COL1A1 and COL3A1 (120180). The bias did not correlate
with the degree of chemical dissimilarity between gly and the
replacement residues, but in some cases a relationship was observed with
the predicted extent of destabilization of the triple helix. Of the
COL1A1-encoded chains, the most destabilizing residues (valine, glutamic
acid, and aspartic acid) and the least destabilizing residue (alanine)
were underrepresented. This bias supported the hypothesis that the level
of triple-helix destabilization determines clinical outcome.

In an extensive review of published and unpublished sources, Marini et
al. (2007) identified and assembled 832 independent mutations in the
type I collagen genes (493 in COL1A1 and 339 in COL1A2). There were 682
substitutions of glycine residues within the triple-helical domains of
the proteins (391 in COL1A1 and 291 in COL1A2) and 150 splice site
mutations (102 in COL1A1 and 48 in COL1A2). One-third of the mutations
that result in glycine substitutions in COL1A1 were lethal, whereas
substitutions in the first 200 residues were nonlethal and had variable
outcomes unrelated to folding or helix stability domains. Two
exclusively lethal regions, helix positions 691-823 and 910-964, aligned
with major ligand binding regions. Mutations in COL1A2 were
predominantly nonlethal (80%), but lethal regions aligned with
proteoglycan bindings sites. Splice site mutations accounted for 20% of
helical mutations, were rarely lethal, and often led to a mild
phenotype.

Rauch et al. (2010) compared the results of genotype analysis and
clinical examination in 161 patients who were diagnosed as having OI
type I, III, or IV according to the Sillence classification (median age:
13 years) and had glycine mutations in the triple helical domain of
alpha-1(I) (n = 67) or alpha-2(I) (n = 94). There were 111 distinct
mutations, of which 38 affected the alpha-1(I) chain and 73 the
alpha-2(I) chain. Serine substitutions were the most frequently
encountered type of mutation in both chains. Overall, the majority of
patients had a phenotypic diagnosis of OI type III or IV, had
dentinogenesis imperfecta and blue sclera, and were born with skeletal
deformities or fractures. Compared with patients with serine
substitutions in alpha-2(I) (n = 40), patients with serine substitutions
in alpha-1(I) (n = 42) on average were shorter (median height z-score
-6.0 vs -3.4; P = 0.005), indicating that alpha-1(I) mutations cause a
more severe phenotype. Height correlated with the location of the
mutation in the alpha-2(I) chain but not in the alpha-1(I) chain.
Patients with mutations affecting the first 120 amino acids at the
N-terminal end of the collagen type I triple helix had blue sclera but
did not have dentinogenesis imperfecta. Among patients from different
families sharing the same mutation, about 90% and 75% were concordant
for dentinogenesis imperfecta and blue sclera, respectively.

Takagi et al. (2011) reported 4 Japanese patients, including 2 unrelated
patients with what the authors called 'classic OI IIC' and 2 sibs with
features of 'OI IIC' but less distortion of the tubular bones (OI dense
bone variant). No consanguinity was reported in their parents. In both
sibs and 1 sporadic patient, they identified heterozygous mutations in
the C-propeptide region of COL1A1 (120150.0069 and 120150.0070,
respectively), whereas no mutation in this region was identified in the
other sporadic patient. Familial gene analysis revealed somatic
mosaicism of the mutation in the clinically unaffected father of the
sibs, whereas their mother and healthy older sister did not have the
mutation. Histologic examination in the 2 sporadic cases showed a
network of broad, interconnected cartilaginous trabeculae with thin
osseous seams in the metaphyseal spongiosa. Thick, cartilaginous
trabeculae (cartilaginous cores) were also found in the diaphyseal
spongiosa. Chondrocyte columnization appeared somewhat irregular. These
changes differed from the narrow and short metaphyseal trabeculae found
in other lethal or severe cases of OI. Takagi et al. (2011) concluded
that heterozygous C-propeptide mutations in the COL1A1 gene may result
in OI IIC with or without twisting of the long bones and that OI IIC
appears to be inherited as an autosomal dominant trait.

CYTOGENETICS

- COL1A1/PDGFB Fusion Gene

Dermatofibrosarcoma protuberans (DFSP; 607907), an infiltrative skin
tumor of intermediate malignancy, presents specific cytogenetic features
such as reciprocal translocations t(17;22)(q22;q13) and supernumerary
ring chromosomes derived from t(17;22). Simon et al. (1997)
characterized the breakpoints from translocations and rings in
dermatofibrosarcoma protuberans and its juvenile form, giant cell
fibroblastoma, on the genomic and RNA levels. They found that these
rearrangements fuse the PDGFB gene (190040) and the COL1A1 gene. Simon
et al. (1997) commented that PDGFB has transforming activity and is a
potent mitogen for a number of cell types, but its role in oncogenic
processes was not fully understood. They noted that neither COL1A1 nor
PDGFB had hitherto been implicated in tumor translocations. The gene
fusions deleted exon 1 of PDGFB and released this growth factor from its
normal regulation; see 190040.0002.

Nakanishi et al. (2007) used RT-PCR to examine the COL1A1/PDGFB
transcript using frozen biopsy specimens from 3 unrelated patients with
DFSP and identified fusion of COL1A1 exon 25, exon 31, and exon 46,
respectively, to exon 2 of the PDGFB gene. Clinical features and
histopathology did not demonstrate any specific characteristics
associated with the different transcripts.

BIOCHEMICAL FEATURES

Gauba and Hartgerink (2008) reported the design of a novel model system
based upon collagen-like heterotrimers that can mimic the glycine
mutations present in either the alpha-1 or alpha-2 chains of type I
collagen. The design utilized an electrostatic recognition motif in 3
chains that can force the interaction of any 3 peptides, including AAA
(all same), AAB (2 same and 1 different), or ABC (all different) triple
helices. Therefore, the component peptides could be designed in such a
way that glycine mutations were present in zero, 1, 2, or all 3 chains
of the triple helix. They reported collagen mutants containing 1 or 2
glycine substitutions with structures relevant to native forms of OI.
Gauba and Hartgerink (2008) demonstrated the difference in thermal
stability and refolding half-life times between triple helices that vary
only in the frequency of glycine mutations at a particular position.

By differential scanning calorimetry and circular dichroism, Makareeva
et al. (2008) measured and mapped changes in the collagen melting
temperature (delta-T(m)) for 41 different glycine substitutions from 47
OI patients. In contrast to peptides, they found no correlation of
delta-T(m) with the identity of the substituting residue but instead
observed regular variations in delta-T(m) with the substitution location
on different triple helix regions. To relate the delta-T(m) map to
peptide-based stability predictions, the authors extracted the
activation energy of local helix unfolding from the reported peptide
data and constructed the local helix unfolding map and tested it by
measuring the hydrogen-deuterium exchange rate for glycine NH residues
involved in interchain hydrogen bonds. Makareeva et al. (2008)
delineated regional variations in the collagen triple helix stability.
Two large, flexible regions deduced from the delta-T(m) map aligned with
the regions important for collagen fibril assembly and ligand binding.
One of these regions also aligned with a lethal region for Gly
substitutions in the alpha-1(I) chain.

ANIMAL MODEL

Pereira et al. (1993) established a line of transgenic mice that
expressed moderate levels of an internally deleted human COL1A1 gene.
The gene construct was modeled after a sporadic in-frame deletion that
produced a lethal variant of OI. About 6% of the transgenic mice had a
lethal phenotype with extensive fractures at birth, and 33% had
fractures but were viable. The remaining 61% of the transgenic mice had
no apparent fractures as assessed by x-ray examination on the day of
birth. Brother-sister matings produced 8 litters in which approximately
40% of the mice had the lethal phenotype, indicating that expression of
the transgene was more lethal in homozygous mice. The shortened collagen
polypeptide chains synthesized from the human transgene were thought to
bind to and produce degradation of the normal collagen genes synthesized
from the normal mouse alleles. Khillan et al. (1994) extended these
studies using an antisense gene. The strategy of specifically inhibiting
expression of a gene with antisense RNA generated from an inverted gene
was introduced in 1984 (Izant and Weintraub, 1984; Mizuno et al., 1984;
and Pestka et al., 1984). Khillan et al. (1994) assembled an antisense
gene that was similar to the internally deleted COL1A1 minigene used by
Pereira et al. (1993) except that the 3-prime half of the gene was
inverted so as to code for an antisense RNA. Transgenic mice expressing
the antisense gene had a normal phenotype, apparently because the
antisense gene contained human sequences instead of mouse sequences. Two
lines of mice expressing the antisense gene were bred to 2 lines of
transgenic mice expressing the minigene. In mice that inherited both
genes, the incidence of the lethal fragile bone phenotype was reduced
from 92 to 27%. The effect of the antisense gene was directly
demonstrated by an increase in the ratio of normal mouse pro-alpha-1(I)
chains to human mini-chains in tissues from mice that inherited both
genes and had a normal phenotype. The results raised the possibility
that chimeric gene constructs that contain intron sequences and in which
only the first half of a gene is inverted may be particularly effective
as antisense genes.

Pereira et al. (1994) used an inbred strain of transgenic mice
expressing a mutated COL1A1 gene to demonstrate interesting features
concerning phenotypic variability and incomplete penetrance. These
phenomena are striking in families with osteogenesis imperfecta and are
usually explained by differences in genetic background or in
environmental factors. The inbred strain of transgenic mice expressing
an internally deleted COL1A1 gene was bred to wildtype mice of the same
strain so that the inheritance of proneness to fracture could be
examined in a homogeneous genetic background. To minimize the effects of
environmental factors, the phenotype was evaluated in embryos that were
removed from the mother one day before term. Examination of stained
skeletons from 51 transgenic embryos from 11 separate litters
demonstrated that approximately 22% had a severe phenotype with
extensive fractures of both long bones and ribs, approximately 51% had a
mild phenotype with fractures of ribs only, and approximately 27% had no
fractures. The ratio of steady-state levels of the mRNA from the
transgene to the level of mRNA from the endogenous gene was the same in
all transgenic embryos. The results demonstrated that the phenotypic
variability and incomplete penetrance were not explained by variation in
genetic background or levels in gene expression. Pereira et al. (1994)
concluded from these results that phenotypic variation may be an
inherent characteristic of the mutated collagen gene.

Pereira et al. (1998) studied a transgenic model of osteogenesis
imperfecta (OI) in mice who expressed a mini-COL1A1 gene containing a
large in-frame deletion. Marrow stromal cells from wildtype mice were
infused into OI-transgenic mice. In mice that were irradiated with
potentially lethal levels or sublethal levels, DNA from the donor marrow
stromal cells was detected consistently in marrow, bone, cartilage, and
lung at either 1 or 2.5 months after the infusion. The DNA also was
detected, but less frequently, in the spleen, brain, and skin. There was
a small but statistically significant increase in both collagen content
and mineral content of bone 1 month after the infusion. In experiments
in which male marrow stromal cells were infused into a female
OI-transgenic mouse, fluorescence in situ hybridization assays for the Y
chromosome indicated that after 2.5 months, donor male cells accounted
for 4 to 19% of the fibroblasts or fibroblast-like cells obtained from
primary cultures of the lung, calvaria, cartilage, long bone, tail, and
skin. The results supported previous suggestions that marrow stromal
cells or related cells in marrow serve as a source for continual renewal
of cells in a number of nonhematopoietic tissues.

Aihara et al. (2003) evaluated intraocular pressure (IOP) in transgenic
mice with a targeted mutation in the Col1a1 gene and found that the mice
had ocular hypertension. The authors suggested an association between
IOP regulation and fibrillar collagen turnover.

The mouse mutation 'abnormal gait-2' (Aga2) was identified in an
N-ethyl-N-nitrosurea mutagenesis screen. Lisse et al. (2008) identified
the Aga2 mutation as a T-to-A transversion within intron 50 of the
Col1a1 gene, which introduced a novel 3-prime splice acceptor site that
resulted in a frameshift. The mutant protein was predicted to have a
novel C terminus that lacked a critical cysteine. Homozygosity for Aga2
was embryonic lethal. Heterozygous Aga2 (Aga2/+) animals showed early
lethality, and surviving heterozygotes had widely variable phenotypes
that included loss of bone mass, fractures, deformity, osteoporosis, and
disorganized trabecular and collagen structures. Abnormal pro-Col1a1
chains accumulated intracellularly in Aga2/+ dermal fibroblasts and were
poorly secreted. Intracellular accumulation of Col1a1 was associated
with induction of an endoplasmic reticulum stress response and apoptosis
characterized by caspase-12 (CASP12; 608633) and caspaser-3 (CASP3;
600636) activation in vitro and in vivo.

*FIELD* AV
.0001
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY97ASP

Byers (1990) provided information about this mutation in osteogenesis
imperfecta type II (166210).

.0002
OSTEOGENESIS IMPERFECTA, TYPE I
COL1A1, GLY94CYS

Starman et al. (1989) described a patient with OI type I (166200) in
whom a population of alpha-1(I) chains had a substitution of cysteine
for glycine at position 94.

.0003
OSTEOGENESIS IMPERFECTA, TYPE IV
COL1A1, GLY175CYS

In a patient with 'moderately severe' OI (166220), de Vries and de Wet
(1986, 1987) found a substitution of cysteine for glycine-175. Four
persons in 3 generations were affected with striking variability in
severity of fractures, deformity, and hearing loss, as well as presence
or absence of blue sclerae and Wormian bones.

.0004
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY391ARG

Bateman et al. (1987) characterized a structural defect of the alpha-1
chain of type I collagen in a baby with the lethal perinatal form of OI
(166210). The glycine residue at position 391 had been replaced by
arginine. The substitution was associated with increased enzymatic
hydroxylation of neighboring regions of the alpha-1 chain. This finding
suggested that the sequence abnormality had interfered with the
propagation of the triple helix across the mutant region. The abnormal
collagen was not incorporated into the more insoluble fraction of bone
collagen. The baby appeared to be heterozygous for the sequence
abnormality, and, since the parents did not show any evidence of the
defect, the authors concluded that the baby had a new mutation. The
amino acid substitution could result from a single nucleotide change in
the codon GGC (glycine) to produce the codon CGC (arginine).

.0005
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, GLY526CYS

In a patient with OI type III (259420), Starman et al. (1989) identified
a population of alpha-1(I) chains in which the glycine at position 526
was replaced by cysteine.

.0006
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY559ASP

Byers (1990) characterized this mutation in a patient with OI type II
(166210).

.0007
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY673ASP

Byers (1990) described this mutation in a patient with type II OI
(166210).

.0008
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY667ARG

This mutation was originally thought to be a substitution of
gly664-to-arg in the alpha-1(I) chain, but in fact alters residue 667
from glycine to arginine, according to Byers (1990). Bateman et al.
(1988) originally described the mutation in osteogenesis imperfecta type
II (166210).

.0009
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY691CYS

Bateman et al. (1988) described this mutation in a patient with type II
OI (166210).

.0010
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY718CYS

Starman et al. (1989) characterized this mutation in a patient with type
II OI (166210).

.0011
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY748CYS

In a fetus with severe OI congenita (166210), Vogel et al. (1987) found
that a single nucleotide change, converting glycine 748 to cysteine in
the alpha-1(I) chain, was responsible for destabilizing the triple helix
and resulted in the lethal disorder. About 80% of the type I procollagen
synthesized by the fibroblasts of the fetus had a decreased thermal
stability. The fibroblasts of both parents were normal, indicating that
this was a new mutation. Vogel et al. (1988) showed that the procollagen
synthesized by the proband's cells is resistant to cleavage by
procollagen N-proteinase, a confirmation-sensitive enzyme. Vogel et al.
(1988) presented several space-filling models that might explain how the
structure of the N-proteinase cleavage site could be affected by an
amino acid substitution over 700 amino acid residues away.

.0012
OSTEOGENESIS IMPERFECTA, TYPE IV
COL1A1, GLY832SER

Marini et al. (1989) characterized this mutation in a patient with OI
type IV (166220). Also see Marini et al. (1993).

.0013
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, GLY844SER

Pack et al. (1989) described this mutation in a patient with OI type III
(259420). An unusual biochemical feature of this mutation was normal
thermal stability of the intact type I collagen; multiple other
mutations in which glycine is replaced result in significantly
diminished thermal stability of the type I collagen molecule.

.0014
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY847ARG

Wallis et al. (1990) described this mutation in OI type II (166210).

.0015
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY883ASP

Cohn et al. (1990) reported this mutation in a patient with OI type II
(166210). Recurrence of the OI type II phenotype in this family was
explained by the finding of both somatic and germline mosaicism for this
mutation in the father of the proband.

.0016
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY904CYS

Constantinou et al. (1989) characterized this mutation in a patient with
the perinatal lethal form of OI (166210). The mutation caused the
synthesis of type I procollagen that was posttranslationally
overmodified, secreted at a decreased rate, and had a decreased thermal
stability. Constantinou et al. (1990) demonstrated that the proband's
mother had the same single base mutation as the proband. However, she
had no fractures and no signs of OI except short stature, slightly blue
sclerae, and mild frontal bossing; as a child, she had the triangular
facies frequently seen in patients with OI. On repeated subculturing,
the proband's fibroblasts grew more slowly than the mother's, but they
continued to synthesize large amounts of the mutated procollagen in
passages 7-14. In contrast, the mother's fibroblasts synthesized
decreasing amounts of the mutated procollagen after passage 11. Also,
the relative amount of the mutated allele in the mother's fibroblasts
decreased with the passage number. In addition, the ratio of the mutated
allele to the normal allele in leukocyte DNA from the mother was half
the value in fibroblast DNA from the proband. Constantinou et al. (1990)
concluded that the simplest interpretation of the findings was that the
mother was mildly affected because she was mosaic for the mutation that
produced a lethal phenotype in 1 of her 3 children. See also Cohn et al.
(1990) and Wallis et al. (1990).

.0017
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY913SER

Byers (1990) described this mutation in OI type II (166210).

.0018
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY988CYS

Steinmann et al. (1984) reported the protein abnormality in a cell line
established from a patient with OI type II (166210). Cohn et al. (1986)
characterized the mutation.

.0019
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY1009SER

Byers (1990) characterized this mutation in OI type II (166210).

.0020
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, EX22DEL

Wallis et al. (1989) described a mutation in COL1A1 resulting in the
deletion of exon 22 during RNA processing. The phenotype was progressive
deforming OI (OI type III; 259420).

.0021
OSTEOGENESIS IMPERFECTA
COL1A1, GLY1017CYS

In a patient with 'moderately severe' OI, Steinmann et al. (1986)
described an abnormal cysteine residue in cyanogen bromide peptide 6 of
an alpha-1(I) chain. According to Byers (1990), the mutation causes
substitution of cysteine for gly1017.

.0022
OSTEOGENESIS IMPERFECTA
COL1A1, GLY1017CYS

Cohn et al. (1988) described a substitution of cysteine for glycine in
the carboxy-terminal region of an alpha-1(I) chain in a patient with
mild OI. Labhard et al. (1988) studied the same patient and identified
the mutation as a heterozygous G-to-T transversion in the COL1A1 gene,
resulting in a gly1017-to-cys (G1017C) substitution.

.0023
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, 9-BP DEL

In a patient with the perinatal lethal form of OI (166210), Wallis et
al. (1989) described the heterozygous deletion of codons 874-876.

.0024
OSTEOGENESIS IMPERFECTA, TYPE I
COL1A1, FS

Willing et al. (1990) reported a frameshift mutation near the 3-prime
end of COL1A1 resulting in the phenotype of OI type I (166200).

.0025
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, 1-BP INS, 4088T

In a baby with the perinatal lethal form of OI (166210), Bateman et al.
(1989) identified heterozygosity for insertion of a single uridine
nucleotide after basepair 4088 of the prepro-alpha-1(I) mRNA of type I
collagen.

Cole et al. (1990) reported further on this patient whose x-ray changes
were most consistent with OI IIB (based on an old classification by
Sillence et al., 1984; see HISTORY in 166210).

.0026
EHLERS-DANLOS SYNDROME, TYPE VIIA
COL1A1, IVS6DS, G-A, -1

In a girl with Ehlers-Danlos syndrome type VIIA (130060) reported by
Cole et al., 1986), Weil et al. (1989) identified a de novo G-to-A
transition in the last nucleotide of exon 6 of the COL1A1 gene,
resulting in the skipping of exon 6 in the mRNA transcripts. The deleted
peptides included those encoding the N-proteinase cleavage site
necessary for proper collagen processing. The patient's unaffected
parents did not carry the mutation. Further confirmation of the
missplicing was obtained by transient expression. The child was born
with bilateral dislocation of the hips and knees and mildly hyperelastic
skin. At 4 years 7 months, her face had a chubby appearance due to
laxity of facial tissues. Height was at the third centile, which was
thought to be due in part to progressive right thoracolumbar scoliosis.
She also had a large inguinal hernia. Collagen fibrils in the skin were
irregular in outline and varied widely in diameter. Cole et al. (1986)
had identified a deletion of 24 amino acids (positions 136-159),
corresponding to exon 6, from the pro-alpha-1(I) protein (Chu et al.,
1984).

D'Alessio et al. (1991) identified the same heterozygous G-to-A mutation
in another child with type VII EDS. The mutation resulted in a
structural defect in the N terminus of the pro-alpha-1(I) collagen. The
G-to-A transition was at the last nucleotide of exon 6 of the COL1A1
gene (which the authors stated corresponded to position -1 of the splice
donor site of intron 6, IVS6DS, G-A, -1). The affected allele produced
transcripts lacking exon 6 sequences and, in lesser amounts, normally
spliced transcripts. The rate of exon 6 skipping was temperature
dependent and appeared to decrease substantially when the patient's
fibroblasts were incubated at 31 degrees C. The mutation was identical
to that described by Weil et al. (1989). This mutation is identical to
that found in COL1A2 (120160.0003).

.0027
MOVED TO 120150.0025
.0028
OSTEOGENESIS IMPERFECTA, TYPE I
COL1A1, GLY178CYS

By chemical cleavage of DNA-DNA heteroduplexes, Valli et al. (1991)
detected a single basepair mismatch in the COL1A1 gene in a patient with
moderately severe osteogenesis imperfecta (166200). The mismatch was
found in about one-half of the heteroduplex molecules formed between the
patient's mRNA and a normal cDNA probe. Sequencing demonstrated a single
G-to-T substitution as the first base of the triplet coding for residue
178 of the triple helical domain of the protein, leading to a
glycine-to-cysteine substitution. Allele-specific oligonucleotide (ASO)
hybridization to amplified DNA confirmed a de novo point mutation in the
proband's genome.

.0029
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY541ASP

See Zhuang et al. (1991).

.0030
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, GLY154ARG

In 2 unrelated individuals with a progressive deforming variety of OI,
Pruchno et al. (1991) found the same new dominant mutation, a
substitution of arginine for glycine-154. The mutation occurred at a CpG
dinucleotide in a manner consistent with deamination of a methylated
cytosine residue. The findings indicated that the type III OI phenotype,
previously thought to be inherited in an autosomal recessive manner
(259420), can result from new dominant mutations in the COL1A1 gene.
Zhuang et al. (1996) found this mutation in a father and his 3 children.

.0031
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY1003SER

In 2 unrelated infants with perinatal lethal OI (166210), Pruchno et al.
(1991) observed a de novo dominant mutation that resulted in
substitution of serine for glycine-1003. This mutation occurred at a CpG
dinucleotide in a manner consistent with deamination of a methylated
cytosine residue. Zhuang et al. (1996) found the same mutation in a
father and his 3 children. The phenotypes of the patients included
manifestations of types I and III/IV osteogenesis imperfecta, but
appeared to be milder than the phenotype of the previously described 2
unrelated patients with the G415C mutation. Zhuang et al. (1996)
speculated that other mutations in the type I collagen genes,
environmental factors, mosaic status of the father, or genes at
different loci might be responsible for the variable phenotype. They
cited the evidence presented by Aitchison et al. (1988) and by Wallis et
al. (1993) from linkage studies, indicating that genes other than the
type 1 collagen genes may be involved in causing or modifying OI. The
finding that allelic variants of the vitamin D receptor gene (277440)
may correlate with low bone density provided another plausible
explanation for a more severe phenotype in some individuals with OI due
to identical mutations in the genes for type I collagen.

.0032
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY637VAL

In a case of lethal osteogenesis imperfecta (166210), Tsuneyoshi et al.
(1991) demonstrated substitution of valine for glycine-637.

.0033
OSTEOGENESIS IMPERFECTA, TYPE III/IV
COL1A1, GLY415CYS

In a male in his late 50s with osteogenesis imperfecta thought to be of
either type III (259420) or type IV (166220), Nicholls et al. (1991)
described heterozygosity for a substitution of cysteine for glycine at
residue 415. Codon 415 was changed from GGC to TGC. The patient's first
recorded fracture occurred at 6 weeks of age. Over the next 16 years he
suffered more than 270 fractures leading to progressive skeletal
deformity. His sclerae were reportedly bluish at birth but had become
paler with age--a characteristic of type III OI. He had developed
conductive hearing loss in his twenties, a feature not previously
described in either type III or type IV. His teeth had been said to have
been yellowish brown. The clinical phenotype and the position of the
mutation conformed to the prediction of Starman et al. (1989) that the
gly-to-cys mutations in the alpha-1(I) chain show a gradient of severity
decreasing from the C-terminus to the N-terminus.

.0034
OSTEOGENESIS IMPERFECTA
COL1A1, GLY85ARG

Deak et al. (1991) reported a 56-year-old male with mild osteogenesis
imperfecta who underwent surgery for severe aortic valve regurgitation.
He was of normal stature, with barrel chest and very pale blue sclera.
Radiologic examination showed kyphoscoliosis and multiple compression
fractures throughout the dorsal spine, although there was no history of
spontaneous fractures. The aortic regurgitation was thought to be part
of the connective tissue abnormality. Enlargement of the aortic root and
mucinous degeneration of the aortic valve such as were found in this
patient had been observed by Weisinger et al. (1975) and others. Deak et
al. (1991) demonstrated substitution of arginine for glycine-85 in one
of the 2 alpha-1(I) procollagen chains.

.0035
OSTEOGENESIS IMPERFECTA, TYPE IIC
COL1A1, GLY1006VAL

In an infant with perinatal lethal osteogenesis imperfecta of the most
severe clinical form, OI IIC (166210), with premature rupture of
membranes, severe antepartum hemorrhage, stillbirth, severe short-limbed
dwarfism, and extreme osteoporosis, Cole et al. (1992) found a
glycine-to-valine substitution at residue 1006 in the triple helical
domain of the alpha-1 chain of type I collagen.

.0036
OSTEOGENESIS IMPERFECTA, TYPE IIA
COL1A1, GLY973VAL

Cole et al. (1992) found substitution of valine for glycine at residue
973 in the triple helical domain of the alpha-1 chain of type I collagen
in an infant born prematurely as a result of premature rupture of
membranes and severe antepartum hemorrhage. The infant had the
radiographic features of OI IIA (166210).

.0037
OSTEOGENESIS IMPERFECTA, TYPE IIA
COL1A1, GLY256VAL

In an infant with OI IIA (166210), Cole et al. (1992) found substitution
of valine for glycine at residue 256 in the triple helical domain of the
alpha-1 chain of type I collagen. Severe osteogenesis imperfecta can
result from substitutions for glycine as far toward the amino-terminal
as position 256. Cole et al. (1992) suggested that the type of glycine
substitution which includes, in addition to valine, cysteine, arginine,
aspartic acid, serine, alanine, tryptophan, and glutamic acid, and the
site and surrounding sequences are probably important factors in
determining the severity of the phenotype, i.e., whether it is OI I/IV,
OI II, or OI III.

.0038
OSTEOPENIC NONFRACTURE SYNDROME
COL1A1, GLY43CYS

Shapiro et al. (1992) described studies of a woman who at the age of 38,
while still premenopausal, was found to have osteopenia, short stature,
hypermobile joints, mild hyperelastic skin, mild scoliosis, and blue
sclerae (see osteogenesis imperfecta type I, 166200). There was no
history of vertebral or appendicular fracture. Hip and vertebral bone
mineral density measurements were consistent with marked fracture risk.
A basepair mismatch between the proband and control COL1A1 cDNA was
detected by chemical cleavage with hydroxylamine:piperidine. Nucleotide
sequence analysis demonstrated a G-to-T substitution in codon 43,
replacing the expected glycine (GGT) residue with cysteine (TGT). Two of
the woman's 4 children were similarly affected.

.0039
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, IVS14DS, G-A, +5

In a fetus with type II OI (166210), Bonadio et al. (1990) demonstrated
homozygosity for a G-to-A transition at the moderately conserved +5
position within the splice donor site of the COL1A1 gene. The mutation
reduced the efficiency of normal splice site selection since the exon
upstream of the mutation was spliced alternatively. The extent of
alternative splicing was sensitive to the temperature at which the
mutant cells were grown, suggesting that the mutation directly affected
spliceosome assembly. The G-to-A transition appeared to be heterozygous
at the level of mRNA and protein because it was unable to disrupt
completely the normal exon 14 splicing. Bonadio et al. (1990) suggested
that low level expression of alternative splicing (as could occur with
heterozygous mutation) might be associated with mild dysfunction of
connective tissue and perhaps, therefore, a phenotype different from
osteogenesis imperfecta. The parents were unrelated and in their
thirties at the time of the offspring's conception; neither parent had
clinical signs or symptoms of OI. The diagnosis of short-limbed dwarfism
was made on the fetus at 5 months of gestation and pregnancy was
terminated electively. At autopsy, the fetus had all the characteristics
of osteogenesis imperfecta congenita. DNA studies in both parents showed
absence of the mutation in all cells studied (Bonadio, 1990). Bonadio
(1990) found evidence suggesting uniparental disomy for chromosome 17. A
new mutation in 1 parent combined with uniparental disomy would explain
the functional homozygosity of the mutation in the fetus. Bonadio (1992)
had not had an opportunity to study the possibility further.

.0040
OSTEOGENESIS IMPERFECTA, TYPE I
COL1A1, GLY901SER

Mottes et al. (1992) identified a GGC (gly) to AGC (ser) transition in
codon 901 of the COL1A1 gene in an 8-year-old boy with repeated
fractures of both femora. Intramedullar rodding had been performed at
the age of 3 years. His mother, 44 years old at the time of his birth,
was short (140 cm) and had mild hypoacusis from age 40 and moderate
osteoporosis but had never had fractures. The mother was likewise
heterozygous for the gly901-to-ser mutation. The mild phenotype was
surprising in light of the usual experience that glycine substitutions
in the C-terminal region of the collagen triple helix cause lethal OI.
The patient was classified as OI type IB on the basis of the absence of
dentinogenesis imperfecta (see 166200).

.0041
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY802VAL

In the surviving child in a family in which the 2 sibs had clinical and
radiologic features typical of lethal OI (166210) (Cohen-Solal et al.,
1991), Bonaventure et al. (1992) used chemical cleavage of cDNA-RNA
heteroduplexes to identify a mismatch in COL1A1 cDNA. The mismatch was
subsequently confirmed by sequencing a PCR-amplified fragment and was
demonstrated to be due to a G-to-T transition in the second base of the
first codon of exon 41 resulting in the substitution of glycine-802 by
valine. The mutation impaired collagen secretion by dermal fibroblasts.
The overmodified chains were retained intracellularly. The mutant allele
was demonstrated in the mother's leukocytes but not in her fibroblasts,
and collagen synthesized by the fibroblasts of both parents was normal.
The findings suggested the presence of somatic and germline mosaicism in
the phenotypically normal mother, explaining the recurrence of OI.

.0042
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, GLY352SER

In a 6.5-year-old girl with 'moderately severe OI' (259420), Marini et
al. (1993) observed substitution of serine for glycine-352 in the
alpha-1 chain of type I collagen. This substitution was produced by a
G-to-A transition in 1 allele.

.0043
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, EX15-16DUP

In an infant with the lethal form of osteogenesis imperfecta (166210),
Cohn et al. (1993) characterized a tandem duplication mutation within
the COL1A1 gene. The structure of the mutation was consistent with
unequal crossing over within a 15-bp region of sequence identity between
exons 14 and 17. The recombination produced a new 81-bp 17/14 hybrid
exon and complete duplication of exons 15 and 16. The sequence implied
duplication of 60 amino acid residues within the triple helical domain
with preservation of the Gly-X-Y repeat. The process was thought to
mimic that by which the triple helical domain of fibrillar collagen
genes arose in evolution by repeated tandem duplication of an ancestral
unit exon.

.0044
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY415SER

In a female infant who died in her first hour of life because of
respiratory failure and showed the features of severe osteogenesis
imperfecta thought to fall between type II (166210) and type III
(259420) of Sillence, Mottes et al. (1993) demonstrated by chemical
cleavage of mismatched bases and subsequent sequencing a G-to-A
transition that caused substitution of gly415 with serine. The same
mutation was found in the clinically normal father's spermatozoa and
lymphocytes. Mosaicism in the father's germline explained the occurrence
in the family of 2 later pregnancies in which OI was documented by
radiographs and ultrasound investigations.

.0045
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY565VAL

In an infant with osteogenesis imperfecta type IIA (166210) born of a
37-year-old mother and a 39-year-old father, Mackay et al. (1993) mapped
the defect in type I collagen to alpha-1 cyanogen bromide peptide 7, a
region corresponding to 271 amino acid residues of either the alpha-1 or
the alpha-2 chain of type I collagen. Polymerase chain reaction
amplification of the corresponding region of the alpha-1(I) mRNA
followed by SSCP analysis of restriction enzyme digests of the PCR
products allowed further mapping of the mutation to a small region of
the COL1A1 gene. A heterozygous G-to-T transversion within the last
splicing codon of exon 32 was identified by DNA sequence analysis. This
mutation had resulted in the substitution of glycine-565 by a valine
residue. The mutation was shown to have occurred de novo.

.0046
OSTEOGENESIS IMPERFECTA, TYPE I
COL1A1, IVS26DS, G-A, +1

Stover et al. (1993) demonstrated defective splicing of mRNA from one
COL1A1 allele in a patient with mild type I OI (166200). Genovese et al.
(1989) had demonstrated that dermal fibroblasts from this patient showed
a novel species of COL1A1 mRNA in the nuclear compartment of cells; that
it was not collinear with a cDNA probe, and, therefore, with the fully
spliced COL1A1 mRNA, was indicated by indirect RNase protection assays.
Stover et al. (1993) showed that a G-to-A transition in the first
position of the donor site of intron 26 resulted in the inclusion of the
entire sequence in the mature mRNA that accumulated in the nuclear
compartment. The retained intron contained an in-frame stop codon and
introduced an out-of-frame insertion within the collagen mRNA producing
stop codons downstream of the insertion. These changes probably
accounted for the failure of the mutant RNA to appear in the cytoplasm.
Unlike other splice site mutations within collagen mRNA that resulted in
exon skipping and a truncated but in-frame RNA transcript, this mutation
did not result in production of a defective COL1A1 chain. Instead, the
mild nature of the disease in this patient reflected failure to process
a defective mRNA and, thus, the absence of a protein product from the
mutant allele.

.0047
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY355ASP

Raghunath et al. (1994) developed a method for early prenatal diagnosis
of molecular disorders involving types I and III collagens. The method
took advantage of the fact that isolated chorionic villi contain
significant amounts of collagen in their extracellular matrix and
synthesize collagens in vitro. They correctly predicted a healthy fetus
and an embryo affected with lethal osteogenesis imperfecta (166210) in
consecutive pregnancies from a couple in which the asymptomatic mother
was a somatic mosaic for a COL1A1 G-to-A transition resulting in
substitution of glycine-355 by aspartic acid. Steinmann (1994) stated
that this is the sixth gly-to-asp substitution in the alpha-1(I) chain,
all of which have been associated with lethal OI regardless of position
of the mutation. This was, furthermore, the ninth example of molecularly
proven mosaicism. The asymptomatic mother was 153 cm tall and was
shorter by 12 to 22 cm than her female first-degree relatives.

.0048
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, GLY862SER

Namikawa et al. (1995) identified a heterozygous gly862-to-ser
substitution in 2 sibs with type III osteogenesis imperfecta (259420).
The mutation was also detected in various paternal tissues; the mutant
allele accounted for approximately 11% of the COL1A1 alleles in blood,
24% of those in fibroblasts, and 43% of those in sperm. The father was
phenotypically normal. The parents were nonconsanguineous. The
first-born child died of respiratory failure at age 3 years after
repeated hospital admissions for recurrent fractures and respiratory
insufficiency. The second-born child was identified as having OI by
ultrasonography at 32 weeks' gestation on the basis of angulated femoral
bones. The father had no history of fractures or other indications of
connective tissue disease. His height was 173 cm (73th percentile for a
30- to 39-year-old Japanese male) and he was taller than his father. His
weight was at the 62nd percentile. Skin, joints, sclera, and teeth were
normal. Germline mosaicism was obviously responsible for the recurrence.
Namikawa et al. (1995) pointed out that there is a cluster of gly-to-ser
substitutions associated with nonlethal phenotypes (gly832-to-ser,
gly844-to-ser, and gly901-to-ser (120150.0040), with gly862-to-ser in
the middle) and that this nonlethal cluster is located between 2 lethal
clusters.

.0049
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, GLY661SER

Nuytinck et al. (1996) observed this mutation in a severely affected
infant with type III OI (259420). The same mutation in the COL1A2 gene
(120160.0030) results in a much milder phenotype, namely post menopausal
osteoporosis.

.0050
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, LEU-PRO, C-TER PROPEPTIDE

Oliver et al. (1996) described unusual molecular findings in a young
girl who presented with severe type III OI (259420). Her otherwise
healthy mother had pale blue sclerae and recurrent joint dislocations of
the ankles, shoulders, knees, elbows, wrists, and neck from 8 years of
age. She suffered dislocation of the left hip during the pregnancy. The
maternal grandfather was 177 cm tall and had recurrent dislocations of
the right elbow and right knee since age 10 years. He had pale blue
sclerae from childhood. He developed progressive deafness of the left
ear, and later Meniere disease. The proposita had dark blue sclerae and
multiple old and new fractures at birth. Subsequently she suffered at
least 200 fractures, mostly of the femurs. At 3 years of age the sclerae
were pale blue. There was a severe pectus carinatum. The skin was
abnormally soft, and there was marked generalized joint laxity. The
broad forehead and triangular shaped face were typical of OI. Teeth and
hearing were normal and she did not bruise easily. Skin fibroblast
cultures from the child produced both normal and posttranslationally
overmodified type I collagen. Cyanogen bromide peptide maps of the
abnormal protein indicated a C-terminal mutation. Examination of the
C-propeptide sequences demonstrated 2 heterozygous single base changes
in the child. One, an A-to-C transversion changing threonine to proline
at residue 29 of the COL1A2 C-propeptide, was also present in the mother
and maternal grandfather but not in 50 unrelated controls. The second
mutation, a T-to-C transition, altered the last amino acid residue of
the COL1A1 C-propeptide from leucine to proline and had occurred de novo
in the affected child. The latter mutation was thought to be responsible
for OI. Oliver et al. (1996) stated that the most frequent cause of
excess posttranslational modification of collagens is the substitution
of glycine in 1 Gly-X-Y repeat unit of the triple helix. No such
mutation was detected in the proband. They commented that the change in
the COL1A2 gene may have been related to the connective tissue
manifestations in the mother and maternal grandfather.

.0051
BONE MINERAL DENSITY VARIATION QUANTITATIVE TRAIT LOCUS
COL1A1, IVS1, 2046G-T (dbSNP rs1800012)

Screening the COL1A1 transcriptional control regions by PCR-SSCP in a
sample of 50 subjects, Grant et al. (1996) found 3 polymorphisms in the
first intron, 2 of which were rare (allele frequency approximately 4%
and 3%) and 1 common (allele frequency approximately 22%). The common
polymorphism was characterized as a G-to-T substitution at the first
base of a consensus site for the transcription factor Sp1 (189906) in
the first intron of COL1A1 (nucleotide 2046). Grant et al. (1996)
devised a PCR-based screen and studied allele distribution in 2
populations of British women, 1 in Aberdeen and 1 in London. They found
that the G/T polymorphism was significantly related to bone mass and
osteoporotic fracture (166710). G/T heterozygotes had significantly
lower bone mineral density (BMD) than G/G homozygotes (SS) in both
populations, and BMD was lower still in G/T homozygotes (ss). The
unfavorable Ss and ss genotypes were over-represented in patients with
severe osteoporosis and vertebral fractures (54%), as compared with
controls (27%) equivalent to a relative risk of 2.97 for vertebral
fracture in individuals who carried the 's' allele. These results were
confirmed and extended by Uitterlinden et al. (1998).

Uitterlinden et al. (1998) studied the Sp1-binding site polymorphism in
1,778 postmenopausal women in the Netherlands and found that compared
with the 1,194 women with the SS genotype, the 526 women with the Ss
genotype had 2% lower bone mineral density at the femoral neck (p =
0.003) and the lumbar spine (p = 0.02); the 58 women with the ss
genotype had reductions of 4% at the femoral neck (p = 0.05) and 6% at
the lumbar spine (p = 0.005). These differences increased with age.
Women with the Ss and ss genotypes were overrepresented among the 111
women who had incident nonvertebral fractures.

Uitterlinden et al. (2001) studied the interaction between polymorphisms
of the vitamin D receptor gene (VDR; 601769) and the Sp1-binding site
polymorphism of COL1A1 and concluded that interlocus interaction is
likely to be an important component of osteoporotic fracture risk.

Sainz et al. (1999) studied the Sp1-binding site polymorphism and
measurements of the size and the density of vertebral bone in 109
healthy prepubertal girls. On average, 22 girls with the Ss genotype and
1 girl with the ss genotype had 6.7% and 33.2% lower cancellous bone
density in the vertebrae, respectively, than girls with the SS genotype.
In contrast, there was no association between the size of the vertebrae
and the COL1A1 genotypes. (One of the authors (Gilsanz, 2008) noted that
the correct ss genotype figure is 33.2% rather than the 49.4% cited in
the 1999 article.)

In an association study involving 3,270 women enrolled in an
osteoporosis screening program, Stewart et al. (2006) analyzed 3 SNPs in
the promoter and intron 1 of the COL1A1 gene (the Sp1-binding site
polymorphism dbSNP rs1800012, which they designated +1245G/T; dbSNP
rs1107946, and dbSNP rs2412298) and their haplotypes. The polymorphisms
were in strong linkage disequilibrium and 3 haplotypes accounted for
more than 95% of the alleles at the COL1A1 locus. Homozygote carriers of
'haplotype 2' had reduced BMD, whereas homozygote carriers of 'haplotype
3' had increased BMD. Stewart et al. (2006) concluded that there is
bidirectional regulation of BMD by the 2 haplotypes in the 5-prime flank
of COL1A1.

In a case-control study of 206 Caucasians with otosclerosis (see 166800)
and 282 Caucasian controls, Chen et al. (2007) identified 2 haplotypes,
composed of 5 SNPs in the COL1A1 gene (dbSNP rs1800012, dbSNP rs9898186,
dbSNP rs2269336, dbSNP rs11327935, and dbSNP rs1107946), that were
significantly associated with otosclerosis. In osteoblast cell lines,
the protective H2 haplotype decreased promoter activity, whereas the
susceptibility H3 haplotype increased promoter activity by affecting
binding of transcription factors to cis-acting elements, suggesting that
increased amounts of collagen alpha-1 homotrimers are causally related
to the development of otosclerosis. Consistent with this hypothesis,
Chen et al. (2007) demonstrated hearing loss in mice from a naturally
occurring mutant strain that only deposits homotrimeric type I collagen.
The authors designated the Sp1-binding site polymorphism, dbSNP
rs1800012, as +1126G/T.

Jin et al. (2009) showed that the previously reported 5-prime
untranslated region (UTR) SNPs in the COL1A1 gene (-1997G-T, dbSNP
rs1107946, 120150.0067; -1663indelT, dbSNP rs2412298, 120150.0068;
+1245G-T, dbSNP rs1800012) affected COL1A1 transcription. Transcription
was 2-fold higher with the osteoporosis-associated G-del-T haplotype
compared with the common G-ins-G haplotype. The region surrounding dbSNP
rs2412298 recognized a complex of proteins essential for osteoblast
differentiation and function including NMP4 (ZNF384; 609951) and Osterix
(SP7; 606633), and the osteoporosis-associated -1663delT allele had
increased binding affinity for this complex. Further studies showed that
haplotype G-del-T had higher binding affinity for RNA polymerase II,
consistent with increased transcription of the G-del-T allele, and there
was a significant inverse association between carriage of G-del-T and
bone mineral density (BMD) in a cohort of 3,270 Caucasian women. Jin et
al. (2009) concluded that common polymorphic variants in the 5-prime UTR
of COL1A1 regulate transcription by affecting DNA-protein interactions,
and that increased levels of transcription correlated with reduced BMD
values in vivo by altering the normal 2:1 ratio between alpha-1(I) and
alpha-2(I) chains.

.0052
OSTEOGENESIS IMPERFECTA, TYPE I, MILD
COL1A1, GLY13ALA

Mayer et al. (1996) described a G-to-C transversion in 1 COL1A1 allele
resulting in a gly13-to-ala substitution in the triple helical domain of
the pro-alpha-1(I) collagen chain. The mutation was found in a
35-year-old woman with a mild form of osteogenesis imperfecta type I
(166200) who presented with spontaneous dissection of the right internal
carotid artery and the right vertebral artery after scuba diving but
without obvious head or neck trauma. Other than a history of easy
bruising and bluish sclerae, she had no evidence of a connective tissue
disorder. There had been no bone fractures or dental problems nor was
there family history of vasculopathy.

.0053
OSTEOGENESIS IMPERFECTA, TYPE II, THIN-BONE TYPE
COL1A1, TRP94CYS

Cole et al. (1996) described an infant with lethal perinatal
osteogenesis imperfecta (166210) resulting from the substitution of
trp94 by cysteine (Y94C) in the C-terminal propeptide of the
pro-alpha-1(I) chain. The infant was born at 38 weeks' gestation with
numerous fractures of the limbs, skull, and ribs, and with subarachnoid
and subdural hemorrhages. Death from respiratory distress occurred
within hours of birth. The limbs and torso were of normal length, shape,
and proportion. All bones were relatively normal in shape and the long
bones showed normal metaphyseal modeling. These clinical and
radiographic features were similar to those observed in another baby
with OI II resulting from a mutation of the C-terminal propeptide of the
pro-alpha-1 chains (Bateman et al., 1989; Cole et al., 1990), but
dissimilar from those reported in babies with OI II resulting from
helical mutations of type 1 collagen. Cole et al. (1996) stated that the
infant's Y94C mutation disturbed procollagen folding and retarded the
formation of disulfide-linked trimers. The endoplasmic reticulum
resident molecular chaperone BiP, which binds to malfolded proteins, was
induced and bound to type I procollagen produced by the OI fibroblasts.
Unassembled mutant pro-alpha-1 chains were also retained in the rough
endoplasmic reticulum.

.0054
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, 562-BP DEL

Wang et al. (1996) identified a novel multiexon deletion in a COL1A1
allele. They examined a 9-year-old girl and her 37-year-old father, both
affected with severe OI type III (259420). SSCP and PCR were used to
identify a 562-bp deletion extending from the last 3 nucleotides of exon
34 to 156 nucleotides from the 3-prime end of intron 36. This deletion
was also detected in the clinically normal grandmother, who was
confirmed to be a mosaic carrier. Three alternative forms of mutant mRNA
resulted from this deletion. One form had a deletion with end points
identical to the genomic deletion, resulting in an in-frame mutant mRNA.
The second in-frame form used the normal exon 32 splice donor and the
exon 37 acceptor. The out-of-frame third form used a cryptic donor site
in exon 34 and the exon 37 acceptor site. Although the in-frame forms of
mRNA constituted 60% of the mRNA, no mutant protein was detected in
cultured fibroblasts or in cultured osteoblasts of the patients.

Cabral and Marini (2004) examined a mosaic carrier in the family
previously reported by Wang et al. (1996), the mother of the 'father.'
She was 67 years old when she died of pneumonia after an intracranial
hemorrhage. Two of her 7 children had severe OI type III. One affected
son died of pneumonia as a child. On physical examination, the mosaic
carrier had normal height (161 cm; 50th percentile for adult women) and
well-proportioned span. The only manifestations of a connective tissue
disorder were blue sclerae and a triangular-shaped facies. She had never
sustained a fracture. Bone histology was normal. Thus, in OI,
substantially normal skeletal growth, density, and histology are
compatible with a 40 to 75% burden of osteoblasts heterozygous for a
COL1A1 mutation. These data were considered encouraging for mesenchymal
stem cell transplantation, since mosaic carriers are a naturally
occurring model for cell therapy.

.0055
OSTEOGENESIS IMPERFECTA, TYPE I
COL1A1, ARG963TER

Korkko et al. (1997) found that 2 unrelated patients with type I
osteogenesis imperfecta (166200) had identical mutations that converted
the codon for arginine-963 from CGA to TGA (stop). Willing et al. (1994)
also reported this nucleotide change in a patient with type 1 OI.

.0056
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY586VAL

Forlino et al. (1994) described type III OI in a patient with a G586V
substitution in the alpha-2 chain of collagen I (120160.0023). Lund et
al. (1997) described the same mutation, a G586V substitution, in the
alpha-1 chain in a case of lethal OI type II (166210). They presented
this as evidence that, perhaps because there are 2 alpha-1 chains and 1
alpha-2 chain in type I collagen, substitutions in the alpha-1 gene have
more serious consequences. They pointed out that identical biochemical
alterations in the same chain are known to have different phenotypic
effects, both within families and between unrelated patients.

.0057
EHLERS-DANLOS SYNDROME, TYPE VIIA
COL1A1, IVS5AS, G-A, -1

In a girl with EDS VIIA (130060), born of a 23-year-old Caucasian father
and a 31-year-old mother of Japanese origin, Byers et al. (1997)
identified a heterozygous G-to-A transition at position -1 of the splice
acceptor site of intron 5 of the COL1A1 gene, resulting in the skipping
of exon 6. She presented at birth with large fontanels, a small
umbilical hernia, joint laxity, contractures of the digits of both
hands, short femurs, pendulous skin folds, and bilateral hip
dislocation. PCR amplification around exon 6 of the alpha-1 cDNA
produced 3 bands, one of a normal size, a second about 15 to 20 bp
smaller, and a third equivalent to the product expected with deletion of
the sequence of the entire exon 6. The sequence of the smaller band
indicated that there was a deletion of 15 bp encoding 5 amino acids
(asn-phe-ala-pro-gln), which included the pepsin-sensitive site
(phe-ala) and the N-proteinase cleavage site (pro-gln).

.0058
OSTEOGENESIS IMPERFECTA, TYPE IV
COL1A1, IVS8DS, G-A, +1

Schwarze et al. (1999) reported a patient thought to have moderately
severe osteogenesis imperfecta type IV (166220). Between ages 10 months
and 9 years, she sustained several dozen spontaneous fractures to the
bones of her legs, hands, and feet. After age 9 years, the fracture
frequency decreased dramatically. At this point, she was growth
retarded, with a height of 112 cm, which corresponded to her adult
height. Her virtual cessation of growth was attributed, in part, to
progressive scoliosis and moderate deformity of her lower limbs. Her
mobility was reduced, and she spent most of her time in a wheelchair.
Her sclerae remained grayish-blue. In this patient, Schwarze et al.
(1999) identified a G-to-A transition at the +1 position of intron 8 of
the COL1A1 gene. They stated that most splice site mutations lead to a
limited array of products, including exon skipping, use of cryptic
splice acceptor or donor sites, and intron inclusion. In the patient
reported by Schwarze et al. (1999), however, the splice site mutation
resulted in the production of several splice products from the mutant
allele. These included 1 in which the upstream exon 7 was extended by 96
nucleotides, others in which either intron 8 or introns 7 and 8 were
retained, 1 in which exon 8 was skipped, and 1 that used a cryptic donor
site in exon 8. To determine the mechanism by which exon 7 redefinition
might occur, Schwarze et al. (1999) examined the order of intron removal
in the region of the mutation by using intron/exon primer pairs to
amplify regions of the precursor nuclear mRNA between exon 5 and exon
10. Removal of introns 5, 6, and 9 was rapid. Removal of intron 8
usually preceded removal of intron 7 in the normal gene, although, in a
small proportion of copies, the order was reversed. The proportion of
abnormal products suggested that exon 7 redefinition, intron 7 plus
intron 8 inclusion, and exon 8 skipping all represented products of the
impaired rapid pathway, whereas the intron 8 inclusion product resulted
from use of the slow intron 7-first pathway. The very low-abundance
cryptic exon 8 donor site product could have arisen from either pathway.
Schwarze et al. (1999) interpreted the results as suggesting that there
is commitment of the pre-mRNA to the 2 pathways, independent of the
presence of the mutation, and that the order and rate of intron removal
are important determinants of the outcome of splice site mutations and
may explain some unusual alterations.

.0059
EHLERS-DANLOS SYNDROME, TYPE I
COL1A1, ARG134CYS

In 2 unrelated patients with classic EDS (130000), Nuytinck et al.
(2000) found the same mutation in the COL1A1 gene. The first patient was
a 5-year-old girl who had been born at near term, after premature
rupture of membranes. She had a history of easy bruising and scarring
after minimal trauma and presented soft velvety, and hyperextensible
skin. In addition, she had atrophic paper scars on the face, elbows,
knees, and shins; ecchymoses on the lower legs; and generalized joint
hyperlaxity. Her facial appearance, which included redundant skin folds
on the eyelids and very soft earlobes, was reminiscent of classic EDS.
The sclerae were white, and x-ray examination indicated that she had no
signs of osteoporosis. The second patient was a 7-year-old boy who had
been born near term and showed hypotonia in the first month of life. An
operation was performed for strabismus. When examined at the age of 5
years, he had typical features of classic EDS, including soft and doughy
skin, moderate skin hyperextensibility, and joint hyperlaxity. In
addition, he had a pronounced tendency for splitting of the skin, easy
bruising, and impaired wound healing. He also presented an unusual
tenderness of the skin and soft tissues, evident when he was touched. He
had pectus excavatum and flat feet. The sclerae were white, and
radiographic examination showed no signs of osteoporosis. Both patients
had an arg134-to-cys substitution in the COL1A1 gene. The arginine
residue was highly conserved and localized to the X position of the
Gly-X-Y triplet. As a consequence, intermolecular disulfide bridges were
formed, resulting in type I collagen aggregates, which were retained in
cells. Whereas substitutions of glycine residues in type I collagen
invariably result in osteogenesis imperfecta, substitutions of
nonglycine residues in type I collagen had not previously been
associated with a human disease. In contrast, arg-to-cys substitutions
in type II collagen had been identified in a variety of
chondrodysplasias (e.g., see 120140.0003, 120140.0016, 120140.0018,
120140.0029).

.0060
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, 9-BP DUP

Cabral et al. (2003) studied the effect of shifting the register of the
collagen helix by a single Gly-X-Y triplet on collagen assembly,
stability, and incorporation into fibrils and matrix. The studies
utilized a triplet duplication in exon 44 of the COL1A1 gene that
occurred in the cDNA and genomic DNA of 2 sibs with lethal OI type II
(166210). The normal allele encodes 3 identical
glycine-alanine-hydroxyproline (gly-ala-hyp) triplets at amino acids
868-876, whereas the mutant allele encodes 4. The register shift delayed
helix formation, causing overmodification. Cabral et al. (2003) showed
that N-propeptide cleavage in procollagen with the triplet duplication
was slower than normal, indicating that the register shift persisted
through the entire helix. The register shift also disrupted
incorporation of mutant collagen into fibrils and matrix. The profound
effects of shifting on chain interaction in the helix and on fibril
formation correlated with the severe clinical consequences. The probands
were the male and female offspring of healthy parents in their twenties.
The mother was entirely normal by clinical history and physical
examination but was shown to be a mosaic carrier with a low percentage
of heterozygous mutant fibroblasts and leukocytes (10 and 15%,
respectively).

.0061
OSTEOGENESIS IMPERFECTA, TYPE IV
COL1A1, 3-BP DEL, 1964GGC

In a family in which the mother and 4 children were affected with
autosomal dominant osteogenesis imperfecta type IV (166220), Lund et al.
(1996) identified an in-frame deletion of nucleotides 1964-1966 (GGC)
from a series of 6 nucleotides (GAG/GCT) encoding codons 437 and 438 in
exon 27 of the COL1A1 gene, resulting in the removal of an alanine
residue at position 438 and a glu437-to-asp (E437D) substitution in the
alpha-1 (I) collagen chain. The father was clinically normal and lacked
the mutation, which was detected by restriction enzyme analysis in all
affected family members. Clinical variation among affected members was
considerable; the most consistent clinical features were reduced height
and extraosseous manifestations of OI. The mother was 136 cm tall and
her 19-year-old daughter 132 cm tall. A 28-year-old son was 137 cm tall
but a 24-year-old son was 162 cm tall and a 31-year-old daughter 151 cm
tall. All had white sclerae and dentinogenesis imperfecta. The heights
of the mother, 2 daughters (31 and 19 years of age), and 2 sons (28 and
24 years of age), were 136, 151, 132, 137, and 162 cm, respectively. The
mother and eldest sib had otosclerosis. The 24-year-old son was
physically active and capable in sports, including contact sports, and
his OI diagnosis was questioned by other members of the family.

.0062
OSTEOGENESIS IMPERFECTA, TYPE I
OSTEOGENESIS IMPERFECTA, TYPE IV, INCLUDED
COL1A1, IVS19DS, G-C, +1

Cabral and Marini (2004) described a family in which the mother was a
mosaic carrier of an IVS19DS+1G-C mutation in the COL1A1 gene and had a
phenotype compatible with OI type I (166200), whereas her 2 sons had
moderately severe OI type IV (166220).

.0063
CAFFEY DISEASE
PRENATAL CORTICAL HYPEROSTOSIS, LETHAL, INCLUDED
COL1A1, ARG836CYS

In affected individuals and obligate carriers from 3 unrelated families
with infantile cortical hyperostosis (114000), Gensure et al. (2005)
identified heterozygosity for a 3040C-T transition in exon 41 of the
COL1A1 gene, predicted to result in an arg836-to-cys (R836C)
substitution within the triple-helical domain of the alpha-1 chain of
type I collagen. None of the affected individuals or obligate carriers
in any of the families had clinical signs of osteogenesis imperfecta,
although some individuals did have joint hyperlaxity and hyperextensible
skin. In 1 family the mutation was not found in the unaffected father,
and in another family it was not found in the unaffected parents or sib
of affected monozygotic twins in whom the mutation was assumed to have
arisen de novo.

In 5 affected members of a Thai family with Caffey disease,
Suphapeetiporn et al. (2007) identified heterozygosity for the R836C
mutation in the COL1A1 gene.

Kamoun-Goldrat et al. (2008) identified heterozygosity for the R836C
mutation in the COL1A1 gene in the pulmonary tissue of a fetus with a
severe form of prenatal cortical hyperostosis (see 114000) from a
terminated pregnancy at 30 weeks' gestation. The authors speculated that
mutation in another gene might also be involved.

.0064
OI/EDS COMBINED SYNDROME
COL1A1, GLY13ASP

Cabral et al. (2005) described a group of patients combining features of
osteogenesis imperfecta (166200) and Ehlers-Danlos syndrome of a
clinical type resembling EDS VII (130060). They showed that the disorder
was due to glycine substitutions or an amino acid deletion within the
N-anchor domain. Mutations within this stabilizing domain induced its
reversible unfolding above 34 degrees centigrade (Makareeva et al.,
2006). One of the substitutions found by Cabral et al. (2005) was gly13
to asp (G13D).

.0065
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, GLY76GLU

In a 13-year-old girl with severe osteogenesis imperfecta type III
(259420), Cabral et al. (2001) identified heterozygosity for a 761G-A
transition in exon 11 of the COL1A1 gene, resulting in a gly76-to-glu
(G76E) substitution. The mutant collagen helices have altered folding,
and thermal denaturation curves demonstrated a decrease in helix
stability. Cabral et al. (2001) stated that this was the first report of
a glutamic acid substitution in the alpha-1(I) chain causing nonlethal
osteogenesis imperfecta.

.0066
EHLERS-DANLOS SYNDROME, TYPE VIIA
COL1A1, IVS5AS, A-T, -2

In a girl with severe EDS VIIA (130060), Giunta et al. (2008) identified
a heterozygous A-to-T transversion in the splice acceptor site of intron
5 of the COL1A1 gene, resulting in the skipping of exon 6. The mutation
resulted in the deletion of amino acids from the N-proteinase cleavage
site. The patient had bilateral hip dislocation, multiple subluxations
of shoulders, elbows, and knees, arthrogryposis, clubfoot, and
hypotonia.

.0067
BONE MINERAL DENSITY VARIATION QUANTITATIVE TRAIT LOCUS
COL1A1, 5-PRIME UTR, G-T, -1997 (dbSNP rs1107946)

See 120150.0051 and Jin et al. (2009).

.0068
BONE MINERAL DENSITY VARIATION QUANTITATIVE TRAIT LOCUS
COL1A1, 5-PRIME UTR, INDEL T, -1663 (dbSNP rs2412298)

See 120150.0051 and Jin et al. (2009).

.0069
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, 1-BP DEL, 4247C

Takagi et al. (2011) reported a sporadic case of what they termed
'classic OI IIC' (see 166210) in a Japanese patient in whom they
identified a 1-bp deletion (4247delC) in the C-propeptide region of the
COL1A1 gene, resulting in a frameshift ().

.0070
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, ALA1387VAL

In 2 Japanese sibs with features of 'OI IIC' (see 166210) but less
distortion of the tubular bones (OI dense bone variant), Takagi et al.
(2011) identified a 4160C-T transition in the C-propeptide region of the
COL1A1 gene, resulting in an ala1387-to-val (A1387V) substitution.
Familial gene analysis revealed somatic mosaicism of the mutation in the
clinically unaffected father of the sibs, whereas their mother and
healthy older sister did not have the mutation.

*FIELD* SA
Bateman et al. (1987); Bonadio et al. (1988); Chu et al. (1985); Cole
et al. (1990); Cole et al. (1987); Dayhoff (1972); Solomon et al.
(1984); Solomon et al. (1984); Thompson et al. (1987)
*FIELD* RF
1. Aihara, M.; Lindsey, J. D.; Weinreb, R. N.: Ocular hypertension
in mice with a targeted type I collagen mutation. Invest. Ophthal.
Vis. Sci. 44: 1581-1585, 2003.

2. Aitchison, K.; Ogilvie, D.; Honeyman, M.; Thompson, E.; Sykes,
B.: Homozygous osteogenesis imperfecta unlinked to collagen I genes. Hum.
Genet. 78: 233-236, 1988.

3. Barsh, G. S.; Byers, P. H.: Reduced secretion of structurally
abnormal type I procollagen in a form of osteogenesis imperfecta. Proc.
Nat. Acad. Sci. 78: 5142-5146, 1981.

4. Bateman, J. F.; Chan, D.; Walker, I. D.; Rogers, J. G.; Cole, W.
G.: Lethal perinatal osteogenesis imperfecta due to the substitution
of arginine for glycine at residue 391 of the alpha-1(I) chain of
type I collagen. J. Biol. Chem. 262: 7021-7027, 1987.

5. Bateman, J. F.; Lamande, S. R.; Dahl, H.-H. M.; Chan, D.; Cole,
W. G.: Substitution of arginine for glycine 664 in the collagen alpha-1(I)
chain in lethal perinatal osteogenesis imperfecta. J. Biol. Chem. 263:
11627-11630, 1988.

6. Bateman, J. F.; Lamande, S. R.; Dahl, H.-H. M.; Chan, D.; Mascara,
T.; Cole, W. G.: A frameshift mutation results in a truncated nonfunctional
carboxyl-terminal pro-alpha-1(I) propeptide of type I collagen in
osteogenesis imperfecta. J. Biol. Chem. 264: 10960-10964, 1989.

7. Bateman, J. F.; Mascara, T.; Chan, D.; Cole, W. G.: A structural
mutation of the collagen alpha-1(I)CB7 peptide in lethal perinatal
osteogenesis imperfecta. J. Biol. Chem. 262: 4445-4451, 1987.

8. Boedtker, H.; Fuller, F.; Tate, V.: The structure of collagen
genes. Int. Rev. Connect. Tissue Res. 10: 1-63, 1983.

9. Bonadio, J.: Personal Communication. Ann Arbor, Mich. 3/1990.

10. Bonadio, J.: Personal Communication. Ann Arbor, Mich. 2/7/1992.

11. Bonadio, J.; Patterson, E.; Smiley, E.: DNA sequence analysis
of perinatal lethal OI mutations.(Abstract) Collagen Rel. Res. 8:
506A, 1988.

12. Bonadio, J.; Ramirez, F.; Barr, M.: An intron mutation in the
human alpha-1(I) collagen gene alters the efficiency of pre-mRNA splicing
and is associated with osteogenesis imperfecta type II. J. Biol.
Chem. 265: 2262-2268, 1990.

13. Bonaventure, J.; Cohen-Solal, L.; Lasselin, C.; Maroteaux, P.
: A dominant mutation in the COL1A1 gene that substitutes glycine
for valine causes recurrent lethal osteogenesis imperfecta. Hum.
Genet. 89: 640-646, 1992.

14. Brookes, A. J.; Sykes, B.; Solomon, E.: Single base pair alterations
as the predominant category of mutation in type I osteogenesis imperfecta.(Letter) J.
Med. Genet. 26: 410, 1989.

15. Byers, P. H.: Personal Communication. Seattle, Wash. 9/23/1993.

16. Byers, P. H.: Personal Communication. Seattle, Wash. 1990.

17. Byers, P. H.; Duvic, M.; Atkinson, M.; Robinow, M.; Smith, L.
T.; Krane, S. M.; Greally, M. T.; Ludman, M.; Matalon, R.; Pauker,
S.; Quanbeck, D.; Schwarze, U.: Ehlers-Danlos syndrome type VIIA
and VIIB result from splice-junction mutations or genomic deletions
that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen. Am.
J. Med. Genet. 72: 94-105, 1997.

18. Byers, P. H.; Starman, B. J.; Cohn, D. H.; Horwitz, A. L.: A
novel mutation causes a perinatal lethal form of osteogenesis imperfecta:
an insertion in one alpha-1(I) collagen allele (COL1A1). J. Biol.
Chem. 263: 7855-7861, 1988.

19. Byrne, D. E. S.; Church, R. L.: Assignment of the genes for mouse
type I procollagen to chromosome 16 using mouse fibroblast-Chinese
hamster somatic cell hybrids. Somat. Cell Genet. 9: 313-331, 1983.

20. Cabral, W. A.; Chernoff, E. J.; Marini, J. C.: G76E substitution
in type I collagen is the first nonlethal glutamic acid substitution
in the alpha-1(I) chain and alters folding of the N-terminal end of
the helix. Molec. Genet. Metab. 72: 326-335, 2001.

21. Cabral, W. A.; Makareeva, E.; Colige, A.; Letocha, A. D.; Ty,
J. M.; Yeowell, H. N.; Pals, G.; Leikin, S.; Marini, J. C.: Mutations
near amino end of alpha-1(I) collagen cause combined osteogenesis
imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide
processing. J. Biol. Chem. 280: 19259-19269, 2005.

22. Cabral, W. A.; Marini, J. C.: High proportion of mutant osteoblasts
is compatible with normal skeletal function in mosaic carriers of
osteogenesis imperfecta. Am. J. Hum. Genet. 74: 752-760, 2004.

23. Cabral, W. A.; Mertts, M. V.; Makareeva, E.; Colige, A.; Tekin,
M.; Pandya, A.; Leikin, S.; Marini, J. C.: Type I collagen triplet
duplication mutation in lethal osteogenesis imperfecta shifts register
of alpha chains throughout the helix and disrupts incorporation of
mutant helices into fibrils and extracellular matrix. J. Biol. Chem. 278:
10006-10012, 2003.

24. Chamberlain, J. R.; Schwarze, U.; Wang, P.-R.; Hirata, R. K.;
Hankenson, K. D.; Pace, J. M.; Underwood, R. A.; Song, K. M.; Sussman,
M.; Byers, P. H.; Russell, D. W.: Gene targeting in stem cells from
individuals with osteogenesis imperfecta. Science 303: 1198-1201,
2004.

25. Chen, W.; Meyer, N. C.; McKenna, M. J.; Pfister, M.; McBride,
D. J., Jr.; Fukushima, K.; Thys, M.; Camp, G. V.; Smith, R. J. H.
: Single-nucleotide polymorphisms in the COL1A1 regulatory regions
are associated with otosclerosis. Clin. Genet. 71: 406-414, 2007.

26. Chu, M.-L.; de Wet, W.; Bernard, M.; Ding, J.-F.; Morabito, M.;
Myers, J.; Williams, C.; Ramirez, F.: Human pro-alpha-1(I) collagen
gene structure reveals evolutionary conservation of a pattern of introns
and exons. Nature 310: 337-340, 1984.

27. Chu, M.-L.; de Wet, W.; Bernard, M.; Ramirez, F.: Fine structural
analysis of the human pro-alpha-1(I) collagen gene: promoter structure,
AluI repeats, and polymorphic transcripts. J. Biol. Chem. 260: 2315-2320,
1985.

28. Church, R. L.; SundarRaj, N.; Rohrbach, D. H.: Gene mapping of
human ocular connective tissue proteins: assignment of the structural
gene for corneal type I procollagen to human chromosome 7 in human
corneal stroma-mouse fibroblast somatic cell hybrids. Invest. Ophthal. 21:
73-79, 1981.

29. Cohen-Solal, L.; Bonaventure, J.; Maroteaux, P.: Dominant mutations
in familial lethal and severe osteogenesis imperfecta. Hum. Genet. 87:
297-301, 1991.

30. Cohn, D. H.; Apone, S.; Eyre, D. R.; Starman, B. J.; Andreassen,
P.; Charbonneau, H.; Nicholls, A. C.; Pope, F. M.; Byers, P. H.:
Substitution of cysteine for glycine within the carboxyl-terminal
telopeptide of the alpha-1 chain of type I collagen produces mild
osteogenesis imperfecta. J. Biol. Chem. 263: 14605-14607, 1988.

31. Cohn, D. H.; Byers, P. H.; Steinmann, B.; Gelinas, R. E.: Lethal
osteogenesis imperfecta resulting from a single nucleotide change
in one human pro-alpha-1(I) collagen allele. Proc. Nat. Acad. Sci. 83:
6045-6047, 1986.

32. Cohn, D. H.; Starman, B. J.; Blumberg, B.; Byers, P. H.: Recurrence
of lethal osteogenesis imperfecta due to parental mosaicism for a
dominant mutation in a human type I collagen gene (COL1A1). Am. J.
Hum. Genet. 46: 591-601, 1990.

33. Cohn, D. H.; Zhang, X.; Byers, P. H.: Homology-mediated recombination
between type I collagen gene exons results in an internal tandem duplication
and lethal osteogenesis imperfecta. Hum. Mutat. 2: 21-27, 1993.

34. Cole, W. G.; Campbell, P. E.; Rogers, J. G.; Bateman, J. F.:
The clinical features of osteogenesis imperfecta resulting from a
non-functional carboxy terminal pro-alpha-1(I) propeptide of type
I procollagen and a severe deficiency of normal type I collagen in
tissues. J. Med. Genet. 27: 545-551, 1990.

35. Cole, W. G.; Chan, D.; Chambers, G. W.; Walker, I. D.; Bateman,
J. F.: Deletion of 24 amino acids from the pro-alpha-1(I) chain of
type I procollagen in a patient with the Ehlers-Danlos syndrome type
VII. J. Biol. Chem. 261: 5496-5503, 1986.

36. Cole, W. G.; Chow, C. W.; Bateman, J. F.; Sillence, D. O.: The
phenotypic features of osteogenesis imperfecta resulting from a mutation
of the carboxyl-terminal pro-alpha-1(I) propeptide that impairs the
assembly of type I procollagen and formation of the extracellular
matrix. J. Med. Genet. 33: 965-967, 1996.

37. Cole, W. G.; Chow, C. W.; Rogers, J. G.; Bateman, J. F.: The
clinical features of three babies with osteogenesis imperfecta resulting
from the substitution of glycine by arginine in the pro alpha-1(I)
chain of type I procollagen. J. Med. Genet. 27: 228-235, 1990.

38. Cole, W. G.; Evans, R.; Sillence, D. O.: The clinical features
of Ehlers-Danlos syndrome type VII due to a deletion of 24 amino acids
from the pro-alpha-1(I) chain of type I procollagen. J. Med. Genet. 24:
698-701, 1987.

39. Cole, W. G.; Patterson, E.; Bonadio, J.; Campbell, P. E.; Fortune,
D. W.: The clinicopathological features of three babies with osteogenesis
imperfecta resulting from the substitution of glycine by valine in
the pro alpha-1(I) chain of type I procollagen. J. Med. Genet. 29:
112-118, 1992.

40. Constantinou, C. D.; Nielsen, K. B.; Prockop, D. J.: A lethal
variant of osteogenesis imperfecta has a single base mutation that
substitutes cysteine for glycine 904 of the alpha-1(I) chain of type
I procollagen: the asymptomatic mother has an unidentified mutation
producing an overmodified and unstable type I procollagen. J. Clin.
Invest. 83: 574-584, 1989.

41. Constantinou, C. D.; Pack, M.; Young, S. B.; Prockop, D. J.:
Phenotypic heterogeneity in osteogenesis imperfecta: the mildly affected
mother of a proband with a lethal variant had the same mutation substituting
cysteine for alpha-1-glycine 904 in a type I procollagen gene (COL1A1). Am.
J. Hum. Genet. 47: 670-679, 1990.

42. D'Alessio, M.; Ramirez, F.; Blumberg, B. D.; Wirtz, M. K.; Rao,
V. H.; Godfrey, M. D.; Hollister, D. W.: Characterization of a COL1A1
splicing defect in a case of Ehlers-Danlos syndrome type VII: further
evidence of molecular homogeneity. Am. J. Hum. Genet. 49: 400-406,
1991.

43. Dalgleish, R.: The human type I collagen mutation database. Nucleic
Acids Res. 25: 181-187, 1997.

44. Dayhoff, M. O.: Atlas of Protein Sequence and Structure. Collagen
alpha-1 chain . Washington: National Biomedical Research Foundation
(pub.) 5: 1972. Pp. D297-D300.

45. Deak, S. B.; Scholz, P. M.; Amenta, P. S.; Constantinou, C. D.;
Levi-Minzi, S. A.; Gonzalez-Lavin, L.; Mackenzie, J. W.: The substitution
of arginine for glycine 85 of the alpha-1(I) procollagen chain results
in mild osteogenesis imperfecta: the mutation provides direct evidence
for three discrete domains of cooperative melting of intact type I
collagen. J. Biol. Chem. 266: 21827-21832, 1991.

46. de Vries, W. N.; de Wet, W. J.: Development and diseases of cartilage
and bone matrix.In: Sen, A.; Thornhill, T.: UCLA Symposia on Molecular
and Cellular Biology--New Series. New York: Alan R. Liss (pub.)
46: 1987.

47. de Vries, W. N.; de Wet, W. J.: The molecular defect in an autosomal
dominant form of osteogenesis imperfecta: synthesis of type I procollagen
containing cysteine in the triple-helical domain of pro-alpha-1(I)
chains. J. Biol. Chem. 261: 9056-9064, 1986.

48. Di Lullo, G. A.; Sweeney, S. M.; Korkko, J.; Ala-Kokko, L.; San
Antonio, J. D.: Mapping the ligand-binding sites and disease-associated
mutations on the most abundant protein in the human, type I collagen. J.
Biol. Chem. 277: 4223-4231, 2002.

49. Driesel, A. J.; Schumacher, A. M.; Flavell, R. A.: A Hind III
restriction site polymorphism in the human collagen alpha-1(I)-like
gene on chromosome no. 7. Hum. Genet. 62: 175-176, 1982.

50. Forlino, A.; Zolezzi, F.; Valli, M.; Pignatti, P. F.; Cetta, G.;
Brunelli, P. C.; Mottes, M.: Severe (type III) osteogenesis imperfecta
due to glycine substitutions in the central domain of the collagen
triple helix. Hum. Molec. Genet. 3: 2201-2206, 1994.

51. Gauba, V.; Hartgerink, J. D.: Synthetic collagen heterotrimers:
structural mimics of wild-type and mutant collagen type I. J. Am.
Chem. Soc. 130: 7509-7515, 2008.

52. Genovese, C.; Brufsky, A.; Shapiro, J.; Rowe, D.: Detection of
mutations in human type I collagen mRNA in osteogenesis imperfecta
by indirect RNase protection. J. Biol. Chem. 264: 9632-9637, 1989.

53. Gensure, R. C.; Makitie, O.; Barclay, C.; Chan, C.; DePalma, S.
R.; Bastepe, M.; Abuzahra, H.; Couper, R.; Mundlos, S.; Sillence,
D.; Ala Kokko, L.; Seidman, J. G.; Cole, W. G.; Juppner, H.: A novel
COL1A1 mutation in infantile cortical hyperostosis (Caffey disease)
expands the spectrum of collagen-related disorders. J. Clin. Invest. 115:
1250-1257, 2005.

54. Gilsanz, V.: Personal Communication. Los Angeles, Calif. 1/8/2008.

55. Giunta, C.; Chambaz, C.; Pedemonte, M.; Scapolan, S.; Steinmann,
B.: The arthrochalasia type of Ehlers-Danlos syndrome (EDS VIIA and
VIIB): the diagnostic value of collagen fibril ultrastructure. (Letter) Am.
J. Med. Genet. 146A: 1341-1346, 2008.

56. Grant, S. F. A.; Reid, D. M.; Blake, G.; Herd, R.; Fogelman, I.;
Ralston, S. H.: Reduced bone density and osteoporosis associated
with a polymorphic Sp1 binding site in the collagen type I-alpha 1
gene. Nature Genet. 14: 203-205, 1996.

57. Huerre, C.; Junien, C.; Weil, D.; Chu, M.-L.; Morabito, M.; Van
Cong, N.; Myers, J. C.; Foubert, C.; Gross, M.-S.; Prockop, D. J.;
Boue, A.; Kaplan, J.-C.; de la Chapelle, A.; Ramirez, F.: Human type
I procollagen genes are located on different chromosomes. Proc. Nat.
Acad. Sci. 79: 6627-6630, 1982.

58. Izant, J. G.; Weintraub, H.: Inhibition of thymidine kinase gene
expression by anti-sense RNA: a molecular approach to genetic analysis. Cell 36:
1007-1015, 1984.

59. Jin, H.; van't Hof, R. J.; Albagha, O. M. E.; Ralston, S. H.:
Promoter and intron 1 polymorphisms of COL1A1 interact to regulate
transcription and susceptibility to osteoporosis. Hum. Molec. Genet. 18:
2729-2738, 2009.

60. Justice, M. J.; Siracusa, L. D.; Gilbert, D. J.; Heisterkamp,
N.; Groffen, J.; Chada, K.; Silan, C. M.; Copeland, N. G.; Jenkins,
N. A.: A genetic linkage map of mouse chromosome 10: localization
of eighteen molecular markers using a single interspecific backcross. Genetics 125:
855-866, 1990.

61. Kamoun-Goldrat, A.; Martinovic, J.; Saada, J.; Sonigo-Cohen, P.;
Razavi, F.; Munnich, A.; Le Merrer, M.: Prenatal cortical hyperostosis
with COL1A1 gene mutation. Am. J. Med. Genet. 146A: 1820-1824, 2008.

62. Khillan, J. S.; Li, S.-W.; Prockop, D. J.: Partial rescue of
a lethal phenotype of fragile bones in transgenic mice with a chimeric
antisense gene directed against a mutated collagen gene. Proc. Nat.
Acad. Sci. 91: 6298-6302, 1994.

63. Klobutcher, L. A.; Ruddle, F. H.: Phenotype stabilisation and
integration of transferred material in chromosome-mediated gene transfer. Nature 280:
657-660, 1979.

64. Korkko, J.; Ala-Kokko, L.; De Paepe, A.; Nuytinck, L.; Earley,
J.; Prockop, D. J.: Analysis of the COL1A1 and COL1A2 genes by PCR
amplification and scanning by conformation-sensitive gel electrophoresis
identifies only COL1A1 mutations in 15 patients with osteogenesis
imperfecta type I: identification of common sequences of null-allele
mutations. Am. J. Hum. Genet. 62: 98-110, 1998.

65. Korkko, J.; Kuivaniemi, H.; Paassilta, P.; Zhuang, J.; Tromp,
G.; DePaepe, A.; Prockop, D. J.; Ala-Kokko, L.: Two new recurrent
nucleotide mutations in the COL1A1 gene in four patients with osteogenesis
imperfecta: about one-fifth are recurrent. Hum. Mutat. 9: 148-156,
1997.

66. Kuivaniemi, H.; Tromp, G.; Prockop, D. J.: Mutations in fibrillar
collagens (types I, II, III, and XI), fibril-associated collagen (type
IX), and network-forming collagen (type X) cause a spectrum of diseases
of bone, cartilage, and blood vessels. Hum. Mutat. 9: 300-315, 1997.

67. Labhard, M. E.; Wirtz, M. K.; Pope, F. M.; Nicholls, A. C.; Hollister,
D. W.: A cysteine for glycine substitution at position 1017 in an
alpha 1(I) chain of type I collagen in a patient with mild dominantly
inherited osteogenesis imperfects. Molec. Biol. Med. 5: 197-207,
1988.

68. Lazarides, E.; Lukens, L. N.: Collagen synthesis on polysomes
in vivo and in vitro. Nature N.B. 232: 37-40, 1971.

69. Lisse, T. S.; Thiele, F.; Fuchs, H.; Hans, W.; Przemeck, G. K.
H.; Abe, K.; Rathkolb, B.; Quintanilla-Martinez, L.; Hoelzlwimmer,
G.; Helfrich, M.; Wolf, E.; Ralston, S. H.; de Angelis, M. H.: ER
stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta. PLoS
Genet. 4: e7, 2008. Note: Electronic Article.

70. Lohmueller, K. E.; Pearce, C. L.; Pike, M.; Lander, E. S.; Hirschhorn,
J. N.: Meta-analysis of genetic association studies supports a contribution
of common variants to susceptibility to common disease. Nature Genet. 33:
177-182, 2003.

71. Long, J.-R.; Liu, P.-Y.; Lu, Y.; Xiong, D.-H.; Zhao, L.-J.; Zhang,
Y.-Y.; Elze, L.; Recker, R. R.; Deng, H.-W.: Association between
COL1A1 gene polymorphisms and bone size in Caucasians. Europ. J.
Hum. Genet. 12: 383-388, 2004.

72. Lund, A. M.; Schwartz, M.; Skovby, F.: Variable clinical expression
in a family with OI type IV due to deletion of three base pairs in
COL1A1. Clin. Genet. 50: 304-309, 1996.

73. Lund, A. M.; Skovby, F.; Schwartz, M.: (G586V) substitutions
in the alpha-1 and alpha-2 chains of collagen I: effect of alpha-chain
stoichiometry on the phenotype of osteogenesis imperfecta? Hum. Mutat. 9:
431-436, 1997.

74. Mackay, K.; Lund, A. M.; Raghunath, M.; Steinmann, B.; Dalgleish,
R.: SSCP detection of a gly565-to-val substitution in the pro-alpha-1(I)
collagen chain resulting in osteogenesis imperfecta type II. Hum.
Genet. 91: 439-444, 1993.

75. Makareeva, E.; Cabral, W. A.; Marini, J. C.; Leikin, S.: Molecular
mechanism of alpha-1(I)-osteogenesis imperfecta/Ehlers-Danlos syndrome:
unfolding of an N-anchor domain at the N-terminal end of the type
I collagen triple helix. J. Biol. Chem. 281: 6463-6470, 2006.

76. Makareeva, E.; Mertz, E. L.; Kuznetsova, N. V.; Sutter, M. B.;
DeRidder, A. M.; Cabral, W. A.; Barnes, A. M.; McBride, D. J.; Marini,
J. C.; Leikin, S.: Structural heterogeneity of type I collagen triple
helix and its role in osteogenesis imperfecta. J. Biol. Chem. 283:
4787-4798, 2008.

77. Marini, J. C.; Forlino, A.; Cabral, W. A.; Barnes, A. M.; San
Antonio, J. D.; Milgrom, S.; Hyland, J. C.; Korkko, J.; Prockop, D.
J.; De Paepe, A.; Coucke, P.; Symoens, S.; and 15 others: Consortium
for osteogenesis imperfecta mutations in the helical domain of type
I collagen: regions rich in lethal mutations align with collagen binding
sites for integrins and proteoglycans. Hum. Mutat. 28: 209-221,
2007.

78. Marini, J. C.; Grange, D. K.; Gottesman, G. S.; Lewis, M. B.;
Koeplin, D. A.: Osteogenesis imperfecta type IV: detection of a point
mutation in one alpha-1(I) collagen allele (COL1A1) by RNA/RNA hybrid
analysis. J. Biol. Chem. 264: 11893-11900, 1989.

79. Marini, J. C.; Lewis, M. B.; Chen, K.: Moderately severe osteogenesis
imperfecta associated with substitutions of serine for glycine in
the alpha-1(I) chain of type I collagen. Am. J. Med. Genet. 45:
241-245, 1993.

80. Mayer, S. A.; Rubin, B. S.; Starman, B. J.; Byers, P. H.: Spontaneous
multivessel cervical artery dissection in a patient with a substitution
of alanine for glycine (G13A) in the alpha-1(I) chain of type I collagen. Neurology 47:
552-556, 1996.

81. Mizuno, T.; Chou, M.; Inouye, M.: A unique mechanism regulating
gene expression: translational inhibition by a complementary RNA transcript
(micRNA). Proc. Nat. Acad. Sci. 81: 1966-1970, 1984.

82. Mottes, M.; Gomez Lira, M. M.; Valli, M.; Scarano, G.; Lonardo,
F.; Forlino, A.; Cetta, G.; Pignatti, P. F.: Paternal mosaicism for
a COL1A1 dominant mutation (alpha-1 ser-415) causes recurrent osteogenesis
imperfecta. Hum. Mutat. 2: 196-204, 1993.

83. Mottes, M.; Sangalli, A.; Valli, M.; Gomez Lira, M.; Tenni, R.;
Buttitta, P.; Pignatti, P. F.; Cetta, G.: Mild dominant osteogenesis
imperfecta with intrafamilial variability: the cause is a serine for
glycine alpha-1(I) 901 substitution in a type-I collagen gene. Hum.
Genet. 89: 480-484, 1992.

84. Munke, M.; Harbers, K.; Jaenisch, R.; Francke, U.: Chromosomal
mapping of four different integration sites of Moloney murine leukemia
virus including the locus for alpha-1(I) collagen in mouse. Cytogenet.
Cell Genet. 43: 140-149, 1986.

85. Nakanishi, G.; Lin, S.-N.; Asagoe, K.; Suzuki, N.; Matsuo, A.;
Tanaka, R.; Makino, E.; Fukimoto, W.; Iwatsuki, K.: A novel fusion
gene of collagen type I alpha 1 (exon 31) and platelet-derived growth
factor B-chain (exon 2) in dermatofibrosarcoma protuberans. Europ.
J. Derm. 17: 217-219, 2007.

86. Namikawa, C.; Suzumori, K.; Fukushima, Y.; Sasaki, M.; Hata, A.
: Recurrence of osteogenesis imperfecta because of paternal mosaicism:
gly862-to-ser substitution in a type I collagen gene (COL1A1). Hum.
Genet. 95: 666-670, 1995.

87. Nicholls, A. C.; Oliver, J.; Renouf, D. V.; Keston, M.; Pope,
F. M.: Substitution of cysteine for glycine at residue 415 of one
allele of the alpha-1(I) chain of type I procollagen in type III/IV
osteogenesis imperfecta. J. Med. Genet. 28: 757-764, 1991.

88. Ninomiya, Y.; Olsen, B. R.: Synthesis and characterization of
cDNA encoding a cartilage-specific short collagen. Proc. Nat. Acad.
Sci. 81: 3014-3018, 1984.

89. Nuytinck, L.; Dalgleish, R.; Spotila, L.; Renard, J.-P.; Van Regemorter,
N.; De Paepe, A.: Substitution of glycine-661 by serine in the alpha-1(I)
and alpha-2(I) chains of type I collagen results in different clinical
and biochemical phenotypes. Hum. Genet. 97: 324-329, 1996.

90. Nuytinck, L.; Freund, M.; Lagae, L.; Pierard, G. E.; Hermanns-Le,
T.; De Paepe, A.: Classical Ehlers-Danlos syndrome caused by a mutation
in type I collagen. Am. J. Hum. Genet. 66: 1398-1402, 2000.

91. Oliver, J. E.; Thompson, E. M.; Pope, F. M.; Nicholls, A. C.:
Mutation in the carboxy-terminal propeptide of the pro-alpha1(I) chain
of type I collagen in a child with severe osteogenesis imperfecta
(OI type III): possible implications for protein folding. Hum. Mutat. 7:
318-326, 1996.

92. Pace, J. M.; Atkinson, M.; Willing, M. C.; Wallis, G.; Byers,
P. H.: Deletions and duplications of Gly-Xaa-Yaa triplet repeats
in the triple helical domains of type I collagen chains disrupt helix
formation and result in several types of osteogenesis imperfecta. Hum.
Mutat. 18: 319-326, 2001.

93. Pack, M.; Constantinou, C. D.; Kalia, K.; Nielsen, K. B.; Prockop,
D. J.: Substitution of serine for alpha-1(I)-glycine 844 in a severe
variant of osteogenesis imperfecta minimally destabilizes the triple
helix of type I procollagen: the effects of glycine substitutions
on thermal stability are either position or amino acid specific. J.
Biol. Chem. 264: 19694-19699, 1989.

94. Pereira, R.; Halford, K.; Sokolov, B. P.; Khillan, J. S.; Prockop,
D. J.: Phenotypic variability and incomplete penetrance of spontaneous
fractures in an inbred strain of transgenic mice expressing a mutated
collagen gene (COL1A1). J. Clin. Invest. 93: 1765-1769, 1994.

95. Pereira, R.; Khillan, J. S.; Helminen, H. J.; Hume, E. L.; Prockop,
D. J.: Transgenic mice expressing a partially deleted gene for type
I procollagen (COL1A1): a breeding line with a phenotype of spontaneous
fractures and decreased bone collagen and mineral. J. Clin. Invest. 91:
709-716, 1993.

96. Pereira, R. F.; O'Hara, M. D.; Laptev, A. V.; Halford, K. W.;
Pollard, M. D.; Class, R.; Simon, D.; Livezey, K.; Prockop, D. J.
: Marrow stromal cells as a source of progenitor cells for nonhematopoietic
tissues in transgenic mice with a phenotype of osteogenesis imperfecta. Proc.
Nat. Acad. Sci. 95: 1142-1147, 1998.

97. Persikov, A. V.; Pillitteri, R. J.; Amin, P.; Schwarze, U.; Byers,
P. H.; Brodsky, B.: Stability related bias in residues replacing
glycines within the collagen triple helix (Gly-Xaa-Yaa) in inherited
connective tissue disorders. Hum. Mutat. 24: 330-337, 2004.

98. Pestka, S.; Daugherty, B. L.; Jung, V.; Hotta, K.; Pestka, R.
K.: Anti-mRNA: specific inhibition of translation of single mRNA
molecules. Proc. Nat. Acad. Sci. 81: 7525-7528, 1984.

99. Pope, F. M.; Nicholls, A. C.; McPheat, J.; Talmud, P.; Owen, R.
: Collagen genes and proteins in osteogenesis imperfecta. J. Med.
Genet. 22: 466-478, 1985.

100. Pruchno, C. J.; Cohn, D. H.; Wallis, G. A.; Willing, M. C.; Starman,
B. J.; Zhang, X.; Byers, P. H.: Osteogenesis imperfecta due to recurrent
point mutations at CpG dinucleotides in the COL1A1 gene of type I
collagen. Hum. Genet. 87: 33-40, 1991.

101. Raghunath, M.; Steinmann, B.; Delozier-Blanchet, C.; Extermann,
P.; Superti-Furga, A.: Prenatal diagnosis of collagen disorders by
direct biochemical analysis of chorionic villus biopsies. Pediat.
Res. 36: 441-448, 1994.

102. Rauch, F.; Lalic, L.; Roughley, P.; Glorieux, F. H.: Genotype-phenotype
correlations in nonlethal osteogenesis imperfecta caused by mutations
in the helical domain of collagen type I. Europ. J. Hum. Genet. 18:
642-647, 2010.

103. Redford-Badwal, D. A.; Stover, M. L.; Valli, M.; McKinstry, M.
B.; Rowe, D. W.: Nuclear retention of COL1A1 messenger RNA identifies
null alleles causing mild osteogenesis imperfecta. J. Clin. Invest. 97:
1035-1040, 1996.

104. Retief, E.; Parker, M. I.; Retief, A. E.: Regional chromosome
mapping of human collagen genes alpha 2(I) and alpha 1(I) (COLIA2
and COLIA1). Hum. Genet. 69: 304-308, 1985.

105. Ruddle, F. H.: Personal Communication. New Haven, Conn. 5/4/1982.

106. Sainz, J.; Van Tornout, J. M.; Sayre, J.; Kaufman, F.; Gilsanz,
V.: Association of collagen type 1 alpha-1 gene polymorphism with
bone density in early childhood. J. Clin. Endocr. Metab. 84: 853-855,
1999.

107. Schnieke, A.; Harbers, K.; Jaenisch, R.: Embryonic lethal mutation
in mice induced by retrovirus insertion into the alpha-1 (I) collagen
gene. Nature 304: 315-320, 1983.

108. Schwarze, U.; Starman, B. J.; Byers, P. H.: Redefinition of
exon 7 in the COL1A1 gene of type I collagen by an intron 8 splice-donor-site
mutation in a form of osteogenesis imperfecta: influence of intron
splice order on outcome of splice-site mutation. Am. J. Hum. Genet. 65:
336-344, 1999.

109. Shapiro, J. R.; Stover, M. L.; Burn, V. E.; McKinstry, M. B.;
Burshell, A. L.; Chipman, S. D.; Rowe, D. W.: An osteopenic nonfracture
syndrome with features of mild osteogenesis imperfecta associated
with the substitution of a cysteine for glycine at triple helix position
43 in the pro-alpha-1(I) chain of type I collagen. J. Clin. Invest. 89:
567-573, 1992.

110. Sillence, D. O.; Barlow, K. K.; Garber, A. P.; Hall, J. G.; Rimoin,
D. L.: Osteogenesis imperfecta type II: delineation of the phenotype
with reference to genetic heterogeneity. Am. J. Med. Genet. 17:
407-423, 1984.

111. Simon, M.-P.; Pedeutour, F.; Sirvent, N.; Grosgeorge, J.; Minoletti,
F.; Coindre, J.-M.; Terrier-Lacombe, M.-J.; Mandahl, N.; Craver, R.
D.; Blin, N.; Sozzi, G.; Turc-Carel, C.; O'Brien, K. P.; Kedra, D.;
Fransson, I.; Guilbaud, C.; Dumanski, J. P.: Deregulation of the
platelet-derived growth factor B-chain gene via fusion with collagen
gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nature
Genet. 15: 95-98, 1997.

112. Sippola-Thiele, M.; Tromp, G. C.; Prockop, D. J.; Ramirez, F.
: Assessment of small polymorphisms in defined human collagen gene
segments. Hum. Genet. 72: 245-247, 1986.

113. Solomon, E.; Hiorns, L.; Sheer, D.; Rowe, D.: Confirmation that
the type I collagen gene on chromosome 17 is COL1A1(alpha-1(I)), using
a human genomic probe. Ann. Hum. Genet. 48: 39-42, 1984.

114. Solomon, E.; Hiorns, L. R.; Cheah, K. S. E.; Parkar, M.; Weiss,
E.; Flavell, R. A.: Assignment of a human alpha-1(I)-like collagen
gene to chromosome 12, by molecular hybridization.(Abstract) Cytogenet.
Cell Genet. 37: 588-589, 1984.

115. Solomon, E.; Sykes, B.: Assignment of alpha-1 (I), alpha-2,
and possibly alpha-1 (III), chains of human collagen to chromosome
7.(Abstract) Cytogenet. Cell Genet. 25: 205, 1979.

116. Starman, B. J.; Eyre, D.; Charbonneau, H.; Harrylock, M.; Weis,
M. A.; Weiss, L.; Graham, J. M., Jr.; Byers, P. H.: Osteogenesis
imperfecta: the position of substitution for glycine by cysteine in
the triple helical domain of the pro-alpha-1(I) chains of type I collagen
determines the clinical phenotype. J. Clin. Invest. 84: 1206-1214,
1989.

117. Steinmann, B.: Personal Communication. Zurich, Switzerland
11/28/1994.

118. Steinmann, B.; Nicholls, A.; Pope, F. M.: Clinical variability
of osteogenesis imperfecta reflecting molecular heterogeneity: cysteine
substitutions in the alpha-1(I) collagen chain producing lethal and
mild forms. J. Biol. Chem. 261: 8958-8964, 1986.

119. Steinmann, B.; Rao, V. H.; Vogel, A.; Bruckner, P.; Gitzelmann,
R.; Byers, P. H.: Cysteine in the triple-helical domain of one allelic
product of the alpha-1(I) gene of type I collagen produces a lethal
form of osteogenesis imperfecta. J. Biol. Chem. 250: 11129-11139,
1984.

120. Stewart, T. L.; Jin, H.; McGuigan, F. E. A.; Albagha, O. M. E.;
Garcia-Giralt, N.; Bassiti, A.; Grinberg, D.; Balcells, S.; Reid,
D. M.; Ralston, S. H.: Haplotypes defined by promoter and intron
1 polymorphisms of the COLIA1 (sic) gene regulate bone mineral density
in women. J. Clin. Endocr. Metab. 91: 3575-3583, 2006.

121. Stover, M. L.; Primorac, D.; Liu, S. C.; McKinstry, M. B.; Rowe,
D. W.: Defective splicing of mRNA from one COL1A1 allele of type
I collagen in nondeforming (type I) osteogenesis imperfecta. J. Clin.
Invest. 92: 1994-2002, 1993.

122. Sundar Raj, C. V.; Church, R. L.; Klobutcher, L. A.; Ruddle,
F. H.: Genetics of the connective tissue proteins: assignment of
the gene for human type I procollagen to chromosome 17 by analysis
of cell hybrids and microcell hybrids. Proc. Nat. Acad. Sci. 74:
4444-4448, 1977.

123. Suphapeetiporn, K.; Tongkobpetch, S.; Mahayosnond, A.; Shotelersuk,
V.: Expanding the phenotypic spectrum of Caffey disease. Clin. Genet. 71:
280-284, 2007.

124. Takagi, M.; Hori, N.; Chinen, Y.; Kurosawa, K.; Tanaka, Y.; Oku,
K.; Sakata, H.; Fukuzawa, R.; Nishimura, G.; Spranger, J.; Hasegawa,
T.: Heterozygous C-propeptide mutations in COL1A1: osteogenesis imperfecta
type IIC and dense bone variant. Am. J. Med. Genet. 155A: 2269-2273,
2011.

125. Thompson, E. M.; Young, I. D.; Hall, C. M.; Pembrey, M. E.:
Recurrence risks and prognosis in severe sporadic osteogenesis imperfecta. J.
Med. Genet. 24: 390-405, 1987.

126. Tromp, G.; Kuivaniemi, H.; Stacey, A.; Shikata, H.; Baldwin,
C. T.; Jaenisch, R.; Prockop, D. J.: Structure of a full-length cDNA
clone for the prepro-alpha-1(I) chain of human type I procollagen. Biochem.
J. 253: 919-922, 1988.

127. Tsipouras, P.; Schwartz, R. C.; Phillips, J. A., III; Willard,
H. F.: A centromere-based linkage group on the long arm of human
chromosome 17. Cytogenet. Cell Genet. 47: 109-110, 1988.

128. Tsuneyoshi, T.; Westerhausen, A.; Constantinou, C. D.; Prockop,
D. J.: Substitutions for glycine alpha-1-637 and glycine alpha-2-694
of type I procollagen in lethal osteogenesis imperfecta: the conformational
strain on the triple helix introduced by a glycine substitution can
be transmitted along the helix. J. Biol. Chem. 266: 15608-15613,
1991.

129. Uitterlinden, A. G.; Burger, H.; Huang, Q.; Yue, F.; McGuigan,
F. E. A.; Grant, S. F. A.; Hofman, A.; van Leeuwen, J. P. T. M.; Pols,
H. A. P.; Ralston, S. H.: Relation of alleles of the collagen type
I-alpha-1 gene to bone density and the risk of osteoporotic fractures
in postmenopausal women. New Eng. J. Med. 338: 1016-1021, 1998.

130. Uitterlinden, A. G.; Weel, A. E. A. M.; Burger, H.; Fang, Y.;
Van Duijn, C. M.; Hofman, A.; Van Leeuwen, J. P. T. M.; Pols, H. A.
P.: Interaction between the vitamin D receptor gene and collagen
type I-alpha-1 gene in susceptibility for fracture. J. Bone Miner.
Res. 16: 379-385, 2001.

131. Valli, M.; Mottes, M.; Tenni, R.; Sangalli, A.; Gomez Lira, M.;
Rossi, A.; Antoniazzi, F.; Cetta, G.; Pignatti, P. F.: A de novo
G to T transversion in a pro-alpha-1(I) collagen gene for a moderate
case of osteogenesis imperfecta: substitution of cysteine for glycine
178 in the triple helical domain. J. Biol. Chem. 266: 1872-1878,
1991.

132. Vogel, B. E.; Doelz, R.; Kadler, K. E.; Hojima, Y.; Engel, J.;
Prockop, D. J.: A substitution of cysteine for glycine 748 of the
alpha-1 chain produces a kink at this site in the procollagen I molecule
and an altered N-proteinase cleavage site over 225 nm away. J. Biol.
Chem. 263: 19249-19255, 1988.

133. Vogel, B. E.; Minor, R. R.; Freund, M.; Prockop, D. J.: A point
mutation in a type I procollagen gene converts glycine 748 of the
alpha-1 chain to cysteine and destabilizes the triple helix in a lethal
variant of osteogenesis imperfecta. J. Biol. Chem. 262: 14737-14744,
1987.

134. Wallis, G. A.; Starman, B. J.; Byers, P. H.: Clinical heterogeneity
of OI explained by molecular heterogeneity and somatic mosaicism.(Abstract) Am.
J. Hum. Genet. 45: A228, 1989.

135. Wallis, G. A.; Starman, B. J.; Zinn, A. B.; Byers, P. H.: Variable
expression of osteogenesis imperfecta in a nuclear family is explained
by somatic mosaicism for a lethal point mutation in the alpha-1(I)
gene (COL1A1) of type I collagen in a parent. Am. J. Hum. Genet. 46:
1034-1040, 1990.

136. Wallis, G. A.; Sykes, B.; Byers, P. H.; Mathew, C. G.; Viljoen,
D.; Beighton, P.: Osteogenesis imperfecta type III: mutations in
the type I collagen structural genes, COL1A1 and COL1A2, are not necessarily
responsible. J. Med. Genet. 30: 492-496, 1993.

137. Wang, Q.; Forlino, A.; Marini, J. C.: Alternative splicing in
COL1A1 mRNA leads to a partial null allele and two in-frame forms
with structural defects in non-lethal osteogenesis imperfecta. J.
Biol. Chem. 271: 28617-28623, 1996.

138. Weil, D.; D'Alessio, M.; Ramirez, F.; de Wet, W.; Cole, W. G.;
Chan, D.; Bateman, J. F.: A base substitution in the exon of a collagen
gene causes alternative splicing and generates a structurally abnormal
polypeptide in a patient with Ehlers-Danlos syndrome type VII. EMBO
J. 8: 1705-1710, 1989.

139. Weisinger, B.; Glassman, E.; Spencer, F. C.; Berger, A.: Successful
aortic valve replacement for aortic regurgitation associated with
osteogenesis imperfecta. Brit. Heart J. 37: 475-477, 1975.

140. Willing, M. C.; Cohn, D. H.; Byers, P. H.: Frameshift mutation
near the 3-prime end of the COL1A1 gene of type I collagen predicts
an elongated pro-alpha-1(I) chain and results in osteogenesis imperfecta
type I. J. Clin. Invest. 85: 282-290, 1990. Note: Erratum: J. Clin.
Invest. 85: following 1338, 1990.

141. Willing, M. C.; Deschenes, S. P.; Scott, D. A.; Byers, P. H.;
Slayton, R. L.; Pitts, S. H.; Arikat, H.; Roberts, E. J.: Osteogenesis
imperfecta type I: molecular heterogeneity for COL1A1 null alleles
of type I collagen. Am. J. Hum. Genet. 55: 638-647, 1994.

142. Willing, M. C.; Deschenes, S. P.; Slayton, R. L.; Roberts, E.
J.: Premature chain termination is a unifying mechanism for COL1A1
null alleles in osteogenesis imperfecta type I cell strains. Am.
J. Hum. Genet. 59: 799-809, 1996.

143. Willing, M. C.; Pruchno, C. J.; Atkinson, M.; Byers, P. H.:
Osteogenesis imperfecta type I is commonly due to a COL1A1 null allele
of type I collagen. Am. J. Hum. Genet. 51: 508-515, 1992.

144. Willing, M. C.; Pruchno, C. J.; Byers, P. H.: Molecular heterogeneity
in osteogenesis imperfecta type I. Am. J. Med. Genet. 45: 223-227,
1993.

145. Willing, M. C.; Slayton, R. L.; Pitts, S. H.; Deschenes, S. P.
: Absence of mutations in the promoter of the COL1A1 gene of type
I collagen in patients with osteogenesis imperfecta type I. J. Med.
Genet. 32: 697-700, 1995.

146. Zhuang, J.; Constantinou, C. D.; Ganguly, A.; Prockop, D. J.
: A single base mutation in type I procollagen (COL1A1) that converts
glycine alpha(1)-541 to aspartate in a lethal variant of osteogenesis
imperfecta: detection of the mutation with a carbodiimide reaction
of DNA heteroduplexes and direct sequencing of products of the PCR. Am.
J. Hum. Genet. 48: 1186-1191, 1991.

147. Zhuang, J.; Tromp, G.; Kuivaniemi, H.; Castells, S.; Prockop,
D. J.: Substitution of arginine for glycine at position 154 of the
alpha-1 chain of type I collagen in a variant of osteogenesis imperfecta:
comparison to previous cases with the same mutation. Am. J. Med.
Genet. 61: 111-116, 1996.

*FIELD* CN
Nara Sobreira - updated: 4/2/2013
Nara Sobreira - updated: 4/11/2011
George E. Tiller - updated: 6/23/2010
Patricia A. Hartz - updated: 5/5/2010
Nara Sobreira - updated: 6/17/2009
Ada Hamosh - updated: 7/9/2008
Cassandra L. Kniffin - updated: 6/18/2008
Marla J. F. O'Neill - updated: 1/24/2008
Marla J. F. O'Neill - updated: 1/2/2008
John A. Phillips, III - updated: 1/2/2008
Cassandra L. Kniffin - updated: 9/21/2007
Cassandra L. Kniffin - updated: 8/29/2007
Cassandra L. Kniffin - updated: 5/17/2007
Marla J. F. O'Neill - updated: 9/29/2006
Anne M. Stumpf - updated: 6/13/2006
Victor A. McKusick - updated: 6/6/2006
Marla J. F. O'Neill - updated: 5/20/2005
Victor A. McKusick - updated: 2/4/2005
Victor A. McKusick - updated: 12/9/2004
Ada Hamosh - updated: 6/11/2004
Marla J. F. O'Neill - updated: 6/2/2004
Victor A. McKusick - updated: 4/21/2004
Jane Kelly - updated: 8/19/2003
Victor A. McKusick - updated: 5/16/2003
Victor A. McKusick - updated: 1/30/2003
Victor A. McKusick - updated: 8/9/2002
Victor A. McKusick - updated: 2/15/2002
Victor A. McKusick - updated: 4/13/2000
Victor A. McKusick - updated: 1/11/2000
John A. Phillips, III - updated: 11/29/1999
Victor A. McKusick - updated: 4/15/1998
Victor A. McKusick - updated: 3/13/1998
Victor A. McKusick - updated: 12/11/1997
Victor A. McKusick - updated: 6/23/1997
Victor A. McKusick - updated: 6/18/1997
Victor A. McKusick - updated: 5/8/1997
Jennifer P. Macke - updated: 4/14/1997
Victor A. McKusick - updated: 3/21/1997
Moyra Smith - updated: 11/12/1996
Orest Hurko - updated: 11/6/1996
Alan F. Scott - updated: 2/20/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 09/27/2013
terry: 4/4/2013
carol: 4/2/2013
carol: 8/6/2012
terry: 5/8/2012
carol: 3/7/2012
carol: 10/6/2011
carol: 4/11/2011
terry: 4/11/2011
carol: 12/3/2010
terry: 11/24/2010
terry: 11/3/2010
carol: 10/12/2010
wwang: 6/30/2010
terry: 6/23/2010
mgross: 5/5/2010
joanna: 4/30/2010
ckniffin: 1/20/2010
carol: 1/11/2010
carol: 7/14/2009
carol: 6/18/2009
terry: 6/17/2009
alopez: 6/2/2009
wwang: 7/18/2008
terry: 7/9/2008
wwang: 7/7/2008
ckniffin: 6/18/2008
carol: 2/20/2008
wwang: 1/29/2008
terry: 1/24/2008
carol: 1/4/2008
carol: 1/2/2008
carol: 12/7/2007
wwang: 10/2/2007
wwang: 9/24/2007
ckniffin: 9/21/2007
wwang: 9/10/2007
ckniffin: 8/29/2007
wwang: 5/22/2007
ckniffin: 5/17/2007
carol: 2/9/2007
wwang: 10/2/2006
terry: 9/29/2006
alopez: 6/13/2006
terry: 6/6/2006
wwang: 10/7/2005
wwang: 10/6/2005
terry: 9/19/2005
carol: 9/2/2005
carol: 5/25/2005
wwang: 5/23/2005
terry: 5/20/2005
wwang: 2/16/2005
wwang: 2/10/2005
terry: 2/4/2005
tkritzer: 1/20/2005
tkritzer: 1/6/2005
terry: 12/9/2004
alopez: 6/15/2004
terry: 6/11/2004
carol: 6/7/2004
terry: 6/2/2004
tkritzer: 4/23/2004
terry: 4/21/2004
carol: 12/26/2003
carol: 8/19/2003
carol: 8/1/2003
mgross: 6/23/2003
tkritzer: 6/4/2003
tkritzer: 5/30/2003
terry: 5/16/2003
alopez: 1/31/2003
terry: 1/30/2003
carol: 9/18/2002
tkritzer: 8/15/2002
tkritzer: 8/13/2002
terry: 8/9/2002
cwells: 2/25/2002
cwells: 2/20/2002
terry: 2/15/2002
carol: 2/20/2001
terry: 1/12/2001
carol: 5/25/2000
carol: 5/12/2000
terry: 4/13/2000
mgross: 2/3/2000
terry: 1/11/2000
alopez: 11/29/1999
psherman: 11/29/1999
mgross: 11/24/1999
dkim: 12/15/1998
dkim: 12/10/1998
dkim: 12/9/1998
terry: 6/18/1998
terry: 5/29/1998
terry: 4/17/1998
terry: 4/15/1998
alopez: 3/17/1998
terry: 3/13/1998
psherman: 3/13/1998
terry: 3/6/1998
mark: 12/20/1997
terry: 12/11/1997
mark: 7/15/1997
jenny: 6/27/1997
alopez: 6/27/1997
terry: 6/23/1997
alopez: 6/21/1997
mark: 6/18/1997
alopez: 5/16/1997
mark: 5/8/1997
alopez: 5/8/1997
alopez: 5/7/1997
alopez: 5/5/1997
alopez: 4/14/1997
terry: 3/21/1997
terry: 3/17/1997
terry: 1/27/1997
jamie: 1/21/1997
mark: 1/15/1997
jenny: 1/14/1997
mark: 11/12/1996
mark: 11/6/1996
terry: 10/23/1996
mark: 10/5/1996
terry: 6/7/1996
terry: 5/30/1996
terry: 3/29/1996
mimman: 3/27/1996
mark: 3/4/1996
mark: 2/27/1996
terry: 2/20/1996
mark: 2/5/1996
terry: 2/1/1996
mark: 10/22/1995
carol: 3/19/1995
terry: 11/1/1994
davew: 8/5/1994
warfield: 4/7/1994
mimadm: 2/11/1994

MIM 130000
*RECORD*
*FIELD* NO
130000
*FIELD* TI
#130000 EHLERS-DANLOS SYNDROME, TYPE I
;;EHLERS-DANLOS SYNDROME, SEVERE CLASSIC TYPE;;
read moreEDS I; EDS1;;
EHLERS-DANLOS SYNDROME, GRAVIS TYPE
*FIELD* TX
A number sign (#) is used with this entry because Ehlers-Danlos syndrome
type I can be caused by mutation in the collagen alpha-1(V) gene
(COL5A1; 120215) on chromosome 9q34 or the collagen alpha-2(V) gene
(COL5A2; 120190) on chromosome 2q31. One patient with EDS I has been
reported to have a mutation in the collagen alpha-1(I) gene (COL1A1;
120150.0059) on chromosome 17q.

DESCRIPTION

The Ehlers-Danlos syndromes (EDS) are a group of heritable connective
tissue disorders that share the common features of skin
hyperextensibility, articular hypermobility, and tissue fragility
(Beighton, 1993).

In the Villefranche classification of EDS (Beighton et al., 1998), 6
main descriptive types were substituted for earlier types numbered with
Roman numerals: classic type (EDS I and EDS II, 130010), hypermobility
type (EDS III, 130020), vascular type (EDS IV, 130050), kyphoscoliosis
type (EDS VI, 225400), arthrochalasia type (EDS VIIA and VIIB, 130060),
and dermatosparaxis type (EDS VIIC, 225410). Six other forms were
listed, including a category of 'unspecified forms.' Major and minor
diagnostic criteria were defined for each type and complemented whenever
possible with laboratory findings.

The main features of classic Ehlers-Danlos syndrome (EDS I and EDS II)
are loose-jointedness and fragile, bruisable skin that heals with
peculiar 'cigarette-paper' scars (Beighton, 1993).

In EDS I, skin involvement is marked and joint laxity is generalized and
gross, with musculoskeletal deformity and diverse orthopedic
complications. Prematurity occurs in approximately 50% of cases.
Internal complications such as aortic and bowel rupture may occasionally
occur. EDS II has all the stigmata of EDS I, but to a minor degree, and
some patients may easily remain undiagnosed (summary by Steinmann et
al., 2002).

CLINICAL FEATURES

Graf (1965) reported a brother and sister with Ehlers-Danlos syndrome
who developed 'spontaneous' carotid-cavernous fistula. Internal
complications included rupture of large vessels, hiatus hernia,
spontaneous rupture of the bowel, and diverticula of the bowel. Retinal
detachment has been observed (Pemberton et al., 1966). Schofield et al.
(1970) reported brother and sister in their 60s who suffered spontaneous
rupture of the colon. They had joint laxity, and both bruised easily and
sustained many lacerations from minor trauma. The father of the 2 sibs
and the son of the brother may have been affected.

Barabas (1966) concluded that most persons with EDS are born prematurely
due to premature rupture of fetal membranes.

Patients with urinary tract infection and other problems related to
bladder diverticulum were reported by Eadie and Wilkins (1967) and by
Zalis and Roberts (1967). Cuckow et al. (1994) described a 4-year-old
boy with huge bladder diverticula complicating type I EDS.

Friedman and Harrod (1982) described a severe form of EDS. The mother
died of dissecting aneurysm of the aorta. Autopsy also showed myxomatous
changes in the mitral and tricuspid valves with redundancy of cusps and
chordae. Both mother and son had large hernias, positional foot
deformities, abnormal thoracic shape, asthma, and severe eczematoid
dermatitis. In an 18-year-old girl with EDS, Mishra et al. (1992)
demonstrated aneurysm of the membranous ventricular septum as well as
mitral valve prolapse. The patient had had lumbosacral fusion for
recurrent spondylolisthesis.

In a large Azerbaijanian village (population about 6,000), Kozlova et
al. (1984) observed a kindred with 92 persons affected with EDS I. One
patient, whose affected parents were cousins, was judged to be
homozygous.

Deodhar and Woolf (1994) suggested that patients with Ehlers-Danlos
syndrome are at unusual risk for postmenopausal osteoporosis.

The minimal diagnostic features for EDS I used in the study of Wenstrup
et al. (1996) were autosomal dominant inheritance, generalized joint
laxity, hyperextensible skin with doughy and velvety texture, and the
presence of widened atrophic scars. The criteria used to distinguish EDS
II from EDS I was the absence of widened atrophic scars in EDS II.

Wenstrup et al. (2002) performed a prospective cohort study on 71
consecutive EDS patients. Twenty of 71, or 28%, had aortic root
dilatation defined as greater than 2 standard deviations above
population-based norms. Fourteen of 42 individuals with the classic form
of EDS (types I and II) and 6 of 29 individuals with the hypermobile
form (type III) had aortic root dilatation, with no gender differences.
Wenstrup et al. (2002) concluded that aortic root dilatation is a common
finding in EDS. However, rates of progression and complication are
unknown.

Nordschow and Marsolais (1969) could demonstrate no abnormality of
shrinkage temperature thermograms of tendon collagen from a hypermobile
joint of an EDS patient. They supported the suggestion of Wechsler and
Fisher (1964) that the defect concerns the amount of collagen produced.
Varadi and Hall (1965) concluded that elastin is normal.

De Felice et al. (2001) studied 4 patients with EDS II and 8 patients
with EDS III (130020), the hypermobile type. They concluded that absence
of the inferior labial frenulum and the lingual frenulum are
characteristics of EDS. Absence of the inferior labial frenulum showed
100% sensitivity and 99.4% specificity; absence of the lingual frenulum
showed 71.4% sensitivity and 100% specificity.

Skin like that in EDS has been observed with a fibrinolytic defect
(134900).

Borck et al. (2010) reported a 42-year-old German man with EDS and
spontaneous rupture of his left common iliac artery, who was negative
for mutation in COL3A1 but was found instead to carry a de novo
heterozygous nonsense mutation (120215.0012) in the COL5A1 gene. The
patient had a history of recurrent inguinal hernias and easy bruising
since childhood; hypertension had been diagnosed 2 years earlier.
Physical examination revealed pigmented scars over bony prominences,
molluscoid pseudotumors at elbows and knees, skin hyperextensibility, as
well as varicose veins, all consistent with EDS. He had no articular
hypermobility or history of joint dislocation, no ophthalmologic
involvement, and no kyphoscoliosis or periodontitis. His parents were
unaffected and did not carry the mutation; however, his daughter and
son, who had smooth skin with a history of easy bruising, which had
raised the suspicion of child abuse by schools and social authorities,
were also heterozygous for the mutation. Borck et al. (2010) stated that
this was the first report of a patient with COL5A1 mutation-positive EDS
and rupture of a large artery, suggesting that arterial rupture might be
a rare complication of classic EDS.

OTHER FEATURES

Voermans et al. (2009) performed a cross-sectional study on the presence
of neuromuscular symptoms in 40 patients with various forms of EDS. Ten
patients each were analyzed with classic EDS, vascular EDS (130050),
hypermobility EDS (130020), and TNX-deficient EDS (606408). Overall,
those with classic EDS and TNX-deficient EDS reported the most
neuromuscular involvement, with muscle weakness, hypotonia, myalgia,
easy fatigability, and intermittent paresthesias, although patients in
all groups reported these features. Physical examination showed mild to
moderate muscle weakness (85%) and reduction of vibration sense (60%)
across all groups. Nerve conduction studies demonstrated axonal
polyneuropathy in 5 (13%) of 39 patients. Needle electromyography showed
myopathic EMG features in 9 (26%) and a mixed neurogenic-myopathic
pattern in 21 (60%) of 35 patients. Muscle ultrasound showed increased
echo intensity in 19 (48%) and atrophy in 20 (50%) of 40 patients. Mild
myopathic features were seen on muscle biopsy of 5 (28%) of 18 patients.
Patients with the hypermobility type EDS caused by TNXB
haploinsufficiency were least affected. Voermans et al. (2009)
postulated that abnormalities in muscle or nerve extracellular matrix
may underlie these findings.

Castori et al. (2010) observed that patients with EDS reported high
levels of chronic pain.

Prontera et al. (2010) reported a 42-year old Italian man with a complex
EDS phenotype caused by a 13.7-Mb de novo heterozygous deletion of
chromosome 2q23.3-q31.2 resulting in deletion of the COL3A1 (120180),
COL5A2, and myostatin (MSTN; 601788) genes. Loss of function mutations
in COL3A1 and COL5A2 cause EDS types IV and I, respectively.
Haploinsufficiency for MSTN results in overgrowth of skeletal muscle.
Due to the monosomy for MSTN, the patient had 'an exceptional
constitutional muscular mass,' without muscle weakness, myalgia, or easy
fatigability. He also had no generalized joint hypomobility or recurrent
joint dislocation; symptoms of EDS were limited to recurrent inguinal
hernias and mild mitral valve prolapse. Prontera et al. (2010)
hypothesized that haploinsufficiency for the MSTN allele exerted a
protective effect again EDS clinical manifestations in this patient. The
findings also indicated that there is direct involvement of muscle
damage in EDS and that care of muscle function in these patients may be
beneficial.

INHERITANCE

EDS I is an autosomal dominant disorder (Wenstrup et al., 1996).

MAPPING

In a 3-generation family with features of Ehlers-Danlos syndrome types I
and II, Burrows et al. (1996) observed tight linkage to the COL5A1 gene
(120215) on chromosome 9q34; a lod score of 4.07 at zero recombination
was calculated. The variation in expression in this family suggested
that EDS types I and II are allelic, and the linkage data supported the
hypothesis that a mutation in COL5A1 can cause both phenotypes.

Wenstrup et al. (1996) reported 2 families in which EDS I cosegregated
with the gene encoding the pro-alpha-1(V) collagen chains (COL5A1). In 2
other families with EDS I, linkage was excluded from both the COL5A1 and
the COL5A2 loci.

In a large Azerbaijanian family with typical clinical manifestations of
EDS I, Sokolov et al. (1991) excluded linkage with 3 collagen genes:
COL1A1 (120150), COL1A2 (120160), and COL3A1 (120180). At least in this
family, the mutation appeared not to lie in any of these genes.

MOLECULAR GENETICS

Wenstrup et al. (1996) demonstrated that affected individuals in one of
the EDS I COL5A1-linked families were heterozygous for a 4-bp deletion
in intron 65 which led to a 234-bp deletion of exon 65 in the processed
mRNA for pro-alpha-1(V) chains (120215.0002). Wenstrup et al. (1996)
noted that the fact that EDS II has been reported to be linked to COL5A1
is indicative that EDS types I and II constitute a clinical and
molecular spectrum. They concluded that EDS I and EDS II are genetically
heterogeneous. They were unable to distinguish clinically between the
COL5A1-linked and unlinked families.

Michalickova et al. (1998) demonstrated that heterozygous mutations in
the COL5A2 gene (e.g., 120190.0001) can also cause type I EDS.

In 2 unrelated patients with classic EDS I, Nuytinck et al. (2000)
identified a heterozygous missense mutation in the COL1A1 gene
(120150.0059).

Malfait et al. (2005) studied fibroblast cultures from 48 patients with
classic EDS for the presence of type V collagen defects. Forty-two (88%)
were heterozygous for an expressed polymorphic variant of COL5A1, and
cDNA from 18 (43%) expressed only 1 COL5A1 allele. In total, 17
mutations leading to a premature stop codon and 5 structural mutations
were identified in the COL5A1 and COL5A2 genes. In 3 patients with a
positive COL5A1 null-allele test, no mutation was found. Overall, in 25
of the 48 patients (52%), an abnormality in type V collagen was
confirmed. Variability in severity of the phenotype was observed, but no
significant genotype-phenotype correlations were found. The relatively
low mutation detection rate suggested that other genes are involved in
classic EDS. Malfait et al. (2005) excluded COL1A1, COL1A2 (120160), and
DCN (125255) as major candidate genes for classic EDS, since they could
find no causal mutation in these genes in a number of patients who
tested negative for COL5A1 and COL5A2.

Pallotta et al. (2004) described a 2-generation family with EDS in which
2 children exhibited features suggestive of EDS I and their mother
exhibited features more suggestive of EDS IV (130050), i.e., she had
thin nose and thin lips, thin translucent skin with prominent
vasculature, and acroosteolysis. No mutation was identified in the
COL3A1 gene (120180), but a deletion mutation was detected in the COL5A1
gene (120215.0011) in all 3 affected family members. The molecular
diagnosis allowed the investigators to categorize the family into the
classic form of EDS, which is associated with a good long-term
prognosis.

Symoens et al. (2012) analyzed COL5A1 and COL5A2 in 126 patients with a
diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen
defect was found, of which 73 were COL5A1 mutations, 13 were COL5A2
mutations, and 7 were COL5A1 null-alleles with mutation unknown. The
majority of the 73 COL5A1 mutations generated a COL5A1 null-allele,
whereas one-third were structural mutations, scattered throughout
COL5A1. All COL5A2 mutations were structural mutations. Reduced
availability of type V collagen appeared to be the major disease-causing
mechanism, besides other intra- and extracellular contributing factors.
All type V collagen defects were identified within a group of 102
patients fulfilling all major clinical Villefranche criteria, that is,
skin hyperextensibility, dystrophic scarring, and joint hypermobility.
No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin
and joint hyperextensibility but lacked dystrophic scarring. Overall,
over 90% of patients fulfilling all major Villefranche criteria for
classic EDS were shown to harbor a type V collagen defect, indicating
that this is the major, if not the only, cause of classic EDS.

- Reviews

Molecular defects in collagen in the several forms of EDS were surveyed
by Prockop and Kivirikko (1984).

HISTORY

Barabas (1967) suggested the existence of 3 distinct types of the
Ehlers-Danlos syndrome. In the classic type, the patients are born
prematurely because of premature rupture of fetal membranes, and have
severe skin and joint involvement but no varicose veins or arterial
ruptures. A second (mild or 'varicose') group is not born prematurely
and, although varicose veins are severe, the skin and joint
manifestations are not. In a third ('arterial') group, bruising,
including spontaneous ecchymoses during menstruation, is a paramount
sign. Skin is soft and transparent but not very extensible, and joint
hypermobility is limited to the hands. Severe and unexplained abdominal
pain is a feature. Repeated arterial ruptures occur in these patients.

According to the original Beighton classification (Beighton, 1970), EDS
I is the severe form of classic Ehlers-Danlos syndrome and EDS II is the
mild form.

According to the classification used by McKusick (1972): EDS I, or
gravis type, is the severe classic form. EDS II (130010), or mitis type,
is the mild classic form. EDS III (130020) is the benign hypermobility
form. EDS IV (130050) is the arterial, ecchymotic or Sack form. EDS V
(305200) is an X-linked form. EDS VI (225400) is the form due to
deficiency of lysyl hydroxylase. EDS VII (225410) is the form due to
deficiency of procollagen protease. EDS VIII (130080) is the form with
accompanying periodontitis. EDS IX (304150) is the form with occipital
horns. EDS X (225310) is the form with a possible fibronectin defect.
EDS XI (147900) is the familial joint instability syndrome.

Steinmann et al. (2002) noted that EDS IX and EDS XI have been
reclassified as occipital horn syndrome and familial joint hypermobility
syndrome, respectively, and that the existence of EDS V, EDS VIII, and
EDS X as distinct entities is questionable.

*FIELD* SA
Beighton et al. (1969); Beighton et al. (1969); Bruno and Narasimhan
(1961); Coventry (1961); Day and Zarafonetis (1961); Goodman et al.
(1962); Grahame and Beighton (1969); Hegreberg et al. (1970); Hines
and Davis (1972); Imahori et al. (1969); Lees et al. (1969); Nuytinck
et al. (2000); Scarpelli and Goodman (1968); Sestak (1962); Vogel
et al. (1979)
*FIELD* RF
1. Barabas, A. P.: Ehlers-Danlos syndrome associated with prematurity
and premature rupture of foetal membranes. Brit. Med. J. 2: 682-684,
1966.

2. Barabas, A. P.: Heterogeneity of the Ehlers-Danlos syndrome: description
of three clinical types and a hypothesis to explain the basic defect(s). Brit.
Med. J. 2: 612-613, 1967.

3. Beighton, P.: The Ehlers-Danlos Syndrome. London: William Heinemann
(pub.) 1970.

4. Beighton, P.: The Ehlers-Danlos syndromes.In: Beighton, P. (ed.)
: McKusick's Heritable Disorders of Connective Tissue. 5th ed. St.
Louis: Mosby 1993. Pp. 189-251.

5. Beighton, P.; De Paepe, A.; Steinmann, B.; Tsipouras, P.; Wenstrup,
R. J.: Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Am.
J. Med. Genet. 77: 31-37, 1998.

6. Beighton, P. H.; Murdoch, J. L.; Votteler, T.: Gastrointestinal
complications of the Ehlers-Danlos syndrome. Gut 10: 1004-1008,
1969.

7. Beighton, P. H.; Price, A.; Lord, J.; Dickson, E. R.: Variants
of the Ehlers-Danlos syndrome: clinical, biochemical, haematological,
and chromosomal features of 100 patients. Ann. Rheum. Dis. 28: 228-245,
1969.

8. Borck, G.; Beighton, P.; Wilhelm, C.; Kohlhase, J.; Kubisch, C.
: Arterial rupture in classic Ehlers-Danlos syndrome with COL5A1 mutation. Am.
J. Med. Genet. 152A: 2090-2093, 2010.

9. Bruno, M. S.; Narasimhan, P.: The Ehlers-Danlos syndrome: a report
of four cases in two generations of a Negro family. New Eng. J. Med. 264:
274-277, 1961.

10. Burrows, N. P.; Nicholls, A. C.; Yates, J. R. W.; Gatward, G.;
Sarathachandra, P.; Richards, A.; Pope, F. M.: The gene encoding
collagen alpha-1(V) (COL5A1) is linked to mixed Ehlers-Danlos syndrome
type I/II. J. Invest. Derm. 106: 1273-1276, 1996.

11. Castori, M.; Camerota, F.; Celletti, C.; Grammatico, P.; Padua,
L.: Quality of life in the classic and hypermobility types of Elhers
(sic)-Danlos syndrome. Neurology 67: 145-146, 2010.

12. Coventry, M. B.: Some skeletal changes in the Ehlers-Danlos syndrome:
a report of two cases. J. Bone Joint Surg. Am. 43: 855-860, 1961.

13. Cuckow, P. M.; Blackhall, R. J. S.; Mouriquand, P. D. E.: Huge
bladder diverticula associated with Ehlers-Danlos syndrome. J. Roy.
Soc. Med. 87: 290-291, 1994.

14. Day, H. J.; Zarafonetis, C. J. D.: Coagulation studies in 4 patients
with Ehlers-Danlos syndrome. Am. J. Med. Sci. 242: 565-573, 1961.

15. De Felice, C.; Toti, P.; Di Maggio, G.; Parrini, S.; Bagnoli,
F.: Absence of the inferior labial and lingual frenula in Ehlers-Danlos
syndrome. Lancet 357: 1500-1502, 2001.

16. Deodhar, A. A.; Woolf, A. D.: Ehlers Danlos syndrome and osteoporosis.
(Letter) Ann. Rheum. Dis. 53: 841-842, 1994.

17. Eadie, D. G. A.; Wilkins, J. L.: Bladder-neck obstruction and
the Ehlers-Danlos syndrome. Brit. J. Urol. 39: 353-358, 1967.

18. Friedman, J. M.; Harrod, M. J. E.: An unusual connective tissue
disease in mother and son: a 'new' type of Ehlers-Danlos syndrome? Clin.
Genet. 21: 168-173, 1982.

19. Goodman, R. M.; Levitsky, J. M.; Friedman, I. A.: The Ehlers-Danlos
syndrome and multiple neurofibromatosis in a kindred of mixed derivations,
with special emphasis on hemostasis in the Ehlers-Danlos syndrome. Am.
J. Med. 32: 976-983, 1962.

20. Graf, C. J.: Spontaneous carotid-cavernous fistula: Ehlers-Danlos
syndrome and related conditions. Arch. Neurol. 13: 662-672, 1965.

21. Grahame, R.; Beighton, P.: Physical properties of the skin in
the Ehlers-Danlos syndrome. Ann. Rheum. Dis. 28: 246-251, 1969.

22. Hegreberg, G. A.; Padgett, G. A.; Otto, R. L.; Henson, J. B.:
A heritable connective tissue disease of dogs and mink resembling
Ehlers-Danlos syndrome of man. I. Skin tensile strength properties. J.
Invest. Derm. 54: 377-380, 1970.

23. Hines, C., Jr.; Davis, W. D.: Ehlers-Danlos syndrome with megaduodenum
and malabsorption syndrome secondary to bacterial overgrowth: a report
of the first case. Am. J. Med. 54: 539-543, 1972.

24. Imahori, S.; Bannerman, R. M.; Graf, C. J.; Brennan, J. C.: Ehlers-Danlos
syndrome with multiple arterial lesions. Am. J. Med. 47: 967-977,
1969.

25. Kozlova, S. I.; Prytkov, A. N.; Blinnikova, O. E.; Sultanova,
F. A.; Bochkova, D. N.: Presumed homozygous Ehlers-Danlos syndrome
type I in a highly inbred kindred. Am. J. Med. Genet. 18: 763-767,
1984.

26. Lees, M. H.; Menashe, V. D.; Sunderland, C. O.; Morgan, C. L.;
Dawson, P. J.: Ehlers-Danlos syndrome associated with multiple pulmonary
artery stenoses and tortuous systemic arteries. J. Pediat. 75: 1031-1036,
1969.

27. Malfait, F.; Coucke, P.; Symoens, S.; Loeys, B.; Nuytinck, L.;
De Paepe, A.: The molecular basis of classic Ehlers-Danlos syndrome:
a comprehensive study of biochemical and molecular findings in 48
unrelated patients. Hum. Mutat. 25: 28-37, 2005.

28. McKusick, V. A.: Heritable Disorders of Connective Tissue.
St. Louis: C. V. Mosby (pub.) (4th ed.): 1972.

29. Michalickova, K.; Susic, M.; Willing, M. C.; Wenstrup, R. J.;
Cole, W. G.: Mutations of the alpha-2(V) chain of type V collagen
impair matrix assembly and produce Ehlers-Danlos syndrome type I. Hum.
Molec. Genet. 7: 249-255, 1998.

30. Mishra, M.; Chambers, J. B.; Grahame, R.: Ventricular septal
aneurysm in a case of Ehlers-Danlos syndrome. Int. J. Cardiol. 36:
369-370, 1992.

31. Nordschow, C. D.; Marsolais, E. B.: Ehlers-Danlos syndrome: some
recent biophysical observations. Arch. Path. 88: 65-68, 1969.

32. Nuytinck, L.; Freund, M.; Lagae, L.; Pierard, G. E.; Hermanns-Le,
T.; De Paepe, A.: Classical Ehlers-Danlos syndrome caused by a mutation
in type I collagen. Am. J. Hum. Genet. 66: 1398-1402, 2000.

33. Pallotta, R.; Ehresmann, T.; Fusilli, P.; De Paepe, A.; Nuytinck,
L.: Discordance between phenotypic appearance and genotypic findings
in a familial case of classical Ehlers-Danlos syndrome. (Letter) Am.
J. Med. Genet. 2004 128A: 436-438, 2004.

34. Pemberton, J. W.; Freeman, H. M.; Schepens, C. L.: Familial retinal
detachment and the Ehlers-Danlos syndrome. Arch. Ophthal. 76: 817-824,
1966.

35. Prockop, D. J.; Kivirikko, K. I.: Heritable diseases of collagen. New
Eng. J. Med. 311: 376-386, 1984.

36. Prontera, P.; Belcastro, V.; Calabresi, P.; Donti, E.: Myostatin
depletion: a therapy for Ehlers-Danlos syndrome? Neurology 67: 147-148,
2010.

37. Scarpelli, D. G.; Goodman, R. M.: Observations on the fine structure
of the fibroblast from a case of Ehlers-Danlos syndrome with the Marfan
syndrome. J. Invest. Derm. 50: 214-219, 1968.

38. Schofield, P. F.; MacDonald, N.; Clegg, J. F.: Familial spontaneous
rupture of the colon: report of two cases. Dis. Colon Rectum 13:
394-396, 1970.

39. Sestak, Z.: Ehlers-Danlos syndrome and cutis laxa: an account
of families in the Oxford area. Ann. Hum. Genet. 25: 313-321, 1962.

40. Sokolov, B. P.; Prytkov, A. N.; Tromp, G.; Knowlton, R. G.; Prockop,
D. J.: Exclusion of COL1A1, COL1A2, and COL3A1 genes as candidate
genes for Ehlers-Danlos syndrome type I in one large family. Hum.
Genet. 88: 125-129, 1991.

41. Steinmann, B.; Royce, P. M.; Superti-Furga, A.: The Ehlers-Danlos
syndrome.In: Royce, P. M.; Steinmann, B. (eds.): Connective Tissue
and its Heritable Disorders: Molecular, Genetic, and Medical Aspects.
2nd ed. New York: Wiley Liss 2002. Pp. 431-524.

42. Symoens, S.; Syx, D.; Malfait, F.; Callewaert, B.; De Backer,
J.; Vanakker, O.; Coucke, P.; De Paepe, A.: Comprehensive molecular
analysis demonstrates type V collagen mutations in over 90% of patients
with classic EDS and allows to refine diagnostic criteria. Hum. Mutat. 33:
1485-1493, 2012.

43. Varadi, D. P.; Hall, D. A.: Cutaneous elastin in Ehlers-Danlos
syndrome. Nature 208: 1224-1225, 1965.

44. Voermans, N. C.; van Alfen, N.; Pillen, S.; Lammens, M.; Schalkwijk,
J.; Zwarts, M. J.; van Rooij, I. A.; Hamel, B. C. J.; van Engelen,
B. G.: Neuromuscular involvement in various types of Ehlers-Danlos
syndrome. Ann. Neurol. 65: 687-697, 2009.

45. Vogel, A.; Holbrook, K. A.; Steinmann, B.; Gitzelmann, R.; Byers,
P. H.: Abnormal collagen fibril structure in the gravis form (type
I) of Ehlers-Danlos syndrome. Lab. Invest. 40: 201-206, 1979.

46. Wechsler, H. L.; Fisher, E. R.: Ehlers-Danlos syndrome: pathologic,
histochemical and electron microscopic observations. Arch. Path. 77:
613-619, 1964.

47. Wenstrup, R. J.; Langland, G. T.; Willing, M. C.; D'Souza, V.
N.; Cole, W. G.: A splice-junction mutation in the region of COL5A1
that codes for the carboxyl propeptide of pro-alpha-1(V) chains results
in the gravis form of the Ehlers-Danlos syndrome (type I). Hum. Molec.
Genet. 5: 1733-1736, 1996.

48. Wenstrup, R. J.; Meyer, R. A.; Lyle, J. S.; Hoechstetter, L.;
Rose, P. S.; Levy, H. P.; Francomano, C. A.: Prevalence of aortic
root dilation in the Ehlers-Danlos syndrome. Genet. Med. 4: 112-117,
2002.

49. Zalis, E. G.; Roberts, D. C.: Ehlers-Danlos syndrome with a hypoplastic
kidney, bladder diverticulum, and diaphragmatic hernia. Arch. Derm. 96:
540-544, 1967.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Short stature

HEAD AND NECK:
[Face];
Narrow maxilla;
[Ears];
Hypermobile;
Lop ears;
[Eyes];
Myopia;
Blue sclerae;
Ectopia lentis;
Epicanthal folds;
[Mouth];
Small, irregularly placed teeth

CARDIOVASCULAR:
[Heart];
Mitral valve prolapse;
Aortic root dilatation

ABDOMEN:
[External features];
Inguinal hernia;
Umbilical hernia;
[Gastrointestinal];
Spontaneous bowel rupture;
Bowel diverticula

SKELETAL:
Osteoarthritis;
[Limbs];
Joint hypermobility;
Joint dislocation (hip, shoulder, elbow, knee, or clavicle);
[Feet];
Pes planus

SKIN, NAILS, HAIR:
[Skin];
Fragile skin;
Easy bruisability;
Cigarette-paper scars;
Wide, thin scars;
Velvety skin;
Poor wound healing;
Molluscoid pseudotumors;
Spheroids

NEUROLOGIC:
[Central nervous system];
Hypotonia in infancy

PRENATAL MANIFESTATIONS:
[Delivery];
Premature birth following premature rupture of fetal membranes

MOLECULAR BASIS:
Caused by mutation in the collagen V, alpha-1 polypeptide gene (COL5A1,
120215.0002);
Caused by mutation in the collagen V, alpha-2 polypeptide gene (COL5A2,
120190.0001)

*FIELD* CN
Ada Hamosh - updated: 4/11/2000
Kelly A. Przylepa - revised: 3/10/2000

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 07/23/2013
joanna: 6/23/2005
joanna: 7/12/2002
joanna: 4/12/2000
joanna: 4/11/2000
kayiaros: 3/13/2000
kayiaros: 3/10/2000

*FIELD* CN
Nara Sobreira - updated: 02/25/2013
Marla J. F. O'Neill - updated: 2/3/2011
Cassandra L. Kniffin - updated: 5/11/2010
Cassandra L. Kniffin - updated: 2/3/2010
Kelly A. Przylepa - updated: 3/15/2007
Victor A. McKusick - updated: 2/4/2005
Ada Hamosh - updated: 3/5/2003
Victor A. McKusick - updated: 4/21/1998
Victor A. McKusick - updated: 4/15/1998
Moyra Smith - updated: 1/29/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 02/25/2013
alopez: 1/20/2012
wwang: 2/8/2011
terry: 2/3/2011
terry: 1/13/2011
wwang: 5/13/2010
ckniffin: 5/11/2010
wwang: 2/17/2010
ckniffin: 2/3/2010
carol: 1/21/2010
carol: 4/25/2007
carol: 4/18/2007
carol: 4/13/2007
joanna: 3/26/2007
carol: 3/15/2007
terry: 5/23/2005
carol: 2/25/2005
wwang: 2/16/2005
wwang: 2/10/2005
terry: 2/4/2005
carol: 12/3/2003
carol: 10/19/2003
carol: 4/4/2003
cwells: 3/6/2003
cwells: 3/5/2003
mcapotos: 7/5/2001
carol: 3/6/2001
terry: 7/25/2000
carol: 5/25/2000
carol: 2/17/2000
terry: 4/30/1999
carol: 11/13/1998
carol: 5/9/1998
terry: 4/21/1998
carol: 4/17/1998
terry: 4/15/1998
mark: 1/29/1997
terry: 1/28/1997
mark: 1/28/1997
terry: 11/6/1996
carol: 2/13/1995
mimadm: 9/24/1994
terry: 8/30/1994
davew: 8/15/1994
warfield: 2/15/1994
carol: 10/26/1993

MIM 130060
*RECORD*
*FIELD* NO
130060
*FIELD* TI
#130060 EHLERS-DANLOS SYNDROME, TYPE VII, AUTOSOMAL DOMINANT
;;EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE;;
read moreEDS VIIA; EDS7A;;
ARTHROCHALASIS MULTIPLEX CONGENITA;;
EDS VII, MUTANT PROCOLLAGEN TYPE
EDS VIIB, INCLUDED; EDS7B, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because Ehlers-Danlos syndrome
type VIIA (EDS VIIA) and type VIIB (EDS VIIB) are caused by mutations in
the COL1A1 (120150) and COL1A2 (120160) genes, respectively. The
mutations causing EDS type VII alter the protease cleavage site in the
alpha-1 or alpha-2 chains of type I collagen, resulting in the inability
of type I procollagen to be converted to collagen. EDS VIIA and EDS VIIB
are autosomal dominant disorders.

Several forms of osteogenesis imperfecta (see, e.g., OI1; 166200) are
also caused by mutations in the COL1A1 and COL1A2 genes.

EDS type VIIC (225410) is an autosomal recessive disorder caused by a
defect in the procollagen protease itself (ADAMTS2; 604539).

DESCRIPTION

EDS type VII is distinguished from the other types of EDS by the
frequency of congenital hip dislocation and extreme joint laxity with
recurrent joint subluxations and minimal skin involvement (Byers et al.,
1997; Giunta et al., 2008).

Beighton et al. (1998) reported on a revised nosology of the
Ehlers-Danlos syndromes, designated the Villefranche classification.
Major and minor diagnostic criteria were defined for each type and
complemented whenever possible with laboratory findings. Six main
descriptive types were substituted for earlier types numbered with Roman
numerals: classic type (EDS I and II), hypermobility type (EDS III),
vascular type (EDS IV), kyphoscoliosis type (EDS VI), arthrochalasia
type (EDS VIIA and VIIB), and dermatosparaxis type (EDS VIIC). Six other
forms were listed, including a category of 'unspecified forms.'

CLINICAL FEATURES

Lichtenstein et al. (1973) reported a patient with arthrochalasis
multiplex congenita, including short stature, small mandible,
considerable hyperextensibility, and increased skin bruising. Although
the patient was originally thought to have deficiency of procollagen
proteinase, Steinmann et al. (1980) found evidence for a structural
mutation in the alpha-2 polypeptide of type I collagen in this patient.
Steinmann et al. (1980) postulated that the mutation rendered the
procollagen resistant to the action of the peptidase that normally
cleaves off the extra piece from the NH2-end. Since equal amounts of
pro-N-alpha-2 and alpha-2 chains were produced, and the parents were
unaffected, the patient's abnormality was presumed to represent a
dominant mutation.

Eyre et al. (1985) and Steinmann et al. (1985) each reported a similar
case of EDS VII.

Cole et al. (1986) reported a 3-month-old girl with type VII EDS. She
was born with bilateral dislocation of the hips and knees and mildly
hyperelastic skin. At 4 years 7 months, her face had a chubby appearance
due to laxity of facial tissues. Height was at the third centile, which
was thought to be due in part to progressive right thoracolumbar
scoliosis. She also had a large inguinal hernia. Collagen fibrils in the
skin were irregular in outline and varied widely in diameter. Studies of
her collagen showed a deletion of 24 amino acids (positions 136-159)
from the pro-alpha-1(I) protein. The deleted segment normally contains
the small globular region of the NH2-propeptide, the procollagen
N-proteinase cleavage site, the NH2-telopeptide, and the first triplet
of the helix of the alpha-1(I) collagen chain. Loss of the procollagen
N-proteinase cleavage site accounted for the persistence of
NH2-propeptide despite normal activity of N-proteinase. Collagen
production by mutant fibroblasts was doubled, possibly due to reduced
feedback inhibition by NH2-propeptide. Neither parent had the deletion,
indicating a de novo event in the child. The deleted peptide
corresponded precisely to the sequence coded by exon 6 of the normal
pro-alpha-1(I) gene (Chu et al., 1984).

Viljoen et al. (1987) reported a family with EDS VII. The mother and her
4 children had generalized articular laxity, joint dislocations and
subluxations, and wormian bones in the skull. The authors suggested that
the last feature may be more common in EDS VII than previously realized.

Nicholls et al. (1991) reported a 29-year-old male with bilateral hip
dislocation at birth and with other features of the Ehlers-Danlos
syndrome type VIIB. The patient's affected daughter was born with
bilateral hip dislocation, joint hyperflexibility, feet in the
equinovarus position, and hyperextensible skin. This was 1 of the few
observations of transmission of this disorder.

Carr et al. (1994) reported a 32-year-old woman with EDS VIIB confirmed
by genetic analysis (120160.0032). She was born with bilateral hip
dislocation, bilateral knee subluxation, and generalized joint
hypermobility, as well as bilateral inguinal hernias and an umbilical
hernia. Throughout her life, she had multiple fractures of the small
bones of her hands and feet following moderate trauma. An affected
brother was born with bilateral hip dislocation which led to subsequent
osteoarthritis of the hips and total hip replacement at age 35. He also
had marked swan neck deformities of his hands and had multiple fractures
of the metacarpals, distal radius, distal ulnar, as well as a fracture
of the patella and olecranon. Frequency of fractures reduced markedly
after his teenage years. Both patients had a depressed nasal bridge.
Electron microscopy of the proband's dermis, as well as deep fascia and
hip joint capsule from the affected brother, showed that collagen
fibrils in transverse section were nearly circular but with irregular
margins. The history of frequent fractures found in this family was
slightly atypical for type VIIB Ehlers-Danlos syndrome and suggested a
phenotypic overlap with osteogenesis imperfecta.

Byers et al. (1997) reported a girl with EDS VIIA born of a 23-year-old
Caucasian father and a 31-year-old mother of Japanese origin. She
presented at birth with large fontanels, a small umbilical hernia, joint
laxity, contractures of the digits of both hands, short femurs, and
pendulous skin folds. Radiographs demonstrated bilateral hip
dislocation. At the age of 5 months, patent and bulging fontanels with
prominent frontal bossing were noted. She had a small chin, deep blue
sclerae, a narrow chest with mild pectus excavatum, and a large
umbilical hernia. Her large joints were hypermobile. Genetic analysis
identified a heterozygous mutation in the COL1A1 gene (120150.0057) that
resulted in the skipping of exon 6.

Byers et al. (1997) reported a family in which 5 individuals spanning 3
generations had EDS VIIB confirmed by genetic analysis (120160.0042).
The proband was a girl referred at age 9 months because of joint laxity
and inability to sit unsupported. Her feet and wrists could be
dorsiflexed 180 degrees, and her skin was soft and hyperextensible.
Radiographs showed bilateral hip dislocations. Because bracing was
unsuccessful in stabilizing her hips, she underwent, at 16 months, open
reduction of both hips, capsular reefing, and varus osteostomies with
casting and bracing. However, the procedures were not successful in
preventing further dislocations. The child's father had bilateral hip
dislocation identified at the age of 1 month; casting and bracing were
not successful. Subluxation of the metacarpal phalangeal joint of 1
thumb, dislocation of the other, and subluxation of the first metatarsal
joints were also present. A brother had bilateral congenital hip
dislocation with unsuccessful correction and was of average height. This
man had a son who was noted to have dislocated hips at 7 weeks of age
together with dislocations of the right elbow, patellas, fingers, and
toes. Radiographs of the paternal grandfather of the index case showed
bilateral hip dislocations; he walked with difficulty, using crutches.
No affected relatives had fractures, dental or hearing abnormalities,
blue sclerae, poor wound healing, or hernias. Based on the clinical
features of 5 additional affected families, Byers et al. (1997)
concluded that fractures should be considered part of the phenotype of
EDS VII.

Giunta et al. (2008) reported a 12-month-old girl who was noted at birth
to have bilateral hip dislocation, subluxations of the shoulders,
elbows, and knees, arthrogryposis of the hands and feet, clubfoot, and
hypotonia. Other features included short stature, frontal bossing,
hypertelorism, depressed nasal bridge, macrostomia, bluish sclerae,
Moderate pectus excavatum, umbilical hernia, and velvety skin. Skin
biopsy showed highly irregular collagen fibrils with variable diameters.
The changes were more pronounced than those observed in EDS VIIB, but
less severe than those present in EDS VIIC. Genetic analysis identified
a heterozygous mutation in the COL1A1 gene (120150.0066), confirming EDS
VIIA. Giunta et al. (2008) emphasized the importance of examining the
collagen fibril ultrastructure for accurate diagnosis.

MOLECULAR GENETICS

In a girl with EDS VIIA reported by Cole et al., 1986), Weil et al.
(1989) identified a de novo heterozygous mutation in the COL1A1 gene
that resulted in the skipping of exon 6 (120150.0026). The deleted
peptides included those encoding the N-proteinase cleavage site
necessary for proper collagen processing. D'Alessio et al. (1991)
identified the same COL1A1 mutation in another child with EDS VIIA.

In a patient with EDS VIIB reported by Steinmann et al. (1985) and Wirtz
et al. (1987), Weil et al. (1988) identified a heterozygous mutation in
the COL1A2 gene (120160.0002) that resulted in the skipping of exon 6
and elimination of the N-proteinase cleavage site necessary for proper
collagen processing.

In a patient with EDS VIIB previously reported by Lichtenstein et al.
(1973) and Steinmann et al. (1980), Weil et al. (1989) identified a de
novo heterozygous mutation in the COL1A2 gene (120160.0003), resulting
in the skipping of exon 6 and deletion of the cleavage site necessary
for proper collagen processing. The expression of the alternative
splicing in this patient was found to be temperature-dependent; cellular
studies showed that missplicing was effectively abolished at 31 degrees
C and gradually increased to 100% at 39 degrees C. This mutation is
identical to that found in COL1A1 (120150.0026).

In a patient with EDS VIIB, Nicholls et al. (1991) identified a
heterozygous mutation in the COL1A2 gene (120160.0021).

In a patient with EDS VIIB previously described by Viljoen et al.
(1987), Watson et al. (1992) identified a heterozygous mutation in the
COL1A2 gene (120160.0021) that resulted in the skipping of exon 6.

In affected members of 6 unrelated families with EDS type VIIB, Byers et
al. (1997) identified heterozygous mutations in the COL1A2 gene (see,
e.g., 120160.0042) that resulted in the skipping of exon 6. Some
patients had fractures, consistent with alterations in mineral
deposition on collagen fibrils in bony tissues. A patient with EDS VIIA
had a more severe phenotype compared to those with EDS VIIB, and
electron microscopy indicated a more severe disruption of collagen
fibrils in EDS VIIA compared to EDS VIIB. Byers et al. (1997) noted that
collagen I contains 2 COL1A1 chains and 1 COL1A2 chain; thus, mutations
in the COL1A1 gene would affect 3/4 of the collagen molecules, whereas
mutations in the COL1A2 gene would affect only half.

NOMENCLATURE

Halila et al. (1986) refer to the enzymatic form of EDS VII as type VIIA
and to the autosomal dominant form as type VIIB--the opposite of the
system used here.

Nusgens et al. (1992) referred to the 2 structural defects of
procollagen polypeptides as EDS VIIA and EDS VIIB for the COL1A1 and
COL1A2 defects, respectively. They used the designation EDS VIIC for the
autosomal recessive enzymatic form.

*FIELD* SA
Byers et al. (1982); Hass and Hass (1958)
*FIELD* RF
1. Beighton, P.; De Paepe, A.; Steinmann, B.; Tsipouras, P.; Wenstrup,
R. J.: Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Am.
J. Med. Genet. 77: 31-37, 1998.

2. Byers, P. H.; Barsh, G. S.; Holbrook, K. A.: Molecular pathology
in inherited disorders of collagen metabolism. Hum. Path. 13: 89-95,
1982.

3. Byers, P. H.; Duvic, M.; Atkinson, M.; Robinow, M.; Smith, L. T.;
Krane, S. M.; Greally, M. T.; Ludman, M.; Matalon, R.; Pauker, S.;
Quanbeck, D.; Schwarze, U.: Ehlers-Danlos syndrome type VIIA and
VIIB result from splice-junction mutations or genomic deletions that
involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen. Am.
J. Med. Genet. 72: 94-105, 1997.

4. Carr, A. J.; Chiodo, A. A.; Hilton, J. M. N.; Chow, C. W.; Hockey,
A.; Cole, W. G.: The clinical features of Ehlers-Danlos syndrome
type VIIB resulting from a base substitution at the splice acceptor
site of intron 5 of the COL1A2 gene. J. Med. Genet. 31: 306-311,
1994.

5. Chu, M.-L.; de Wet, W.; Bernard, M.; Ding, J.-F.; Morabito, M.;
Myers, J.; Williams, C.; Ramirez, F.: Human pro-alpha-1(I) collagen
gene structure reveals evolutionary conservation of a pattern of introns
and exons. Nature 310: 337-340, 1984.

6. Cole, W. G.; Chan, D.; Chambers, G. W.; Walker, I. D.; Bateman,
J. F.: Deletion of 24 amino acids from the pro-alpha-1(I) chain of
type I procollagen in a patient with the Ehlers-Danlos syndrome type
VII. J. Biol. Chem. 261: 5496-5503, 1986.

7. D'Alessio, M.; Ramirez, F.; Blumberg, B. D.; Wirtz, M. K.; Rao,
V. H.; Godfrey, M. D.; Hollister, D. W.: Characterization of a COL1A1
splicing defect in a case of Ehlers-Danlos syndrome type VII: further
evidence of molecular homogeneity. Am. J. Hum. Genet. 49: 400-406,
1991.

8. Eyre, D. R.; Shapiro, F. D.; Aldridge, J. F.: A heterozygous collagen
defect in a variant of the Ehlers-Danlos syndrome type VII. J. Biol.
Chem. 260: 11322-11329, 1985.

9. Giunta, C.; Chambaz, C.; Pedemonte, M.; Scapolan, S.; Steinmann,
B.: The arthrochalasia type of Ehlers-Danlos syndrome (EDS VIIA and
VIIB): the diagnostic value of collagen fibril ultrastructure. (Letter) Am.
J. Med. Genet. 146A: 1341-1346, 2008.

10. Halila, R.; Steinmann, B.; Peltonen, L.: Processing of types
I and III procollagen in Ehlers-Danlos syndrome type VII. Am. J.
Hum. Genet. 39: 222-231, 1986.

11. Hass, J.; Hass, R.: Arthrochalasis multiplex congenita. J. Bone
Joint Surg. Am. 40: 663-674, 1958.

12. Lichtenstein, J. R.; Martin, G. R.; Kohn, L. D.; Byers, P. H.;
McKusick, V. A.: Defect in conversion of procollagen to collagen
in a form of Ehlers-Danlos syndrome. Science 182: 298-299, 1973.

13. Nicholls, A. C.; Oliver, J.; Renouf, D. V.; McPheat, J.; Palan,
A.; Pope, F. M.: Ehlers-Danlos syndrome type VII: a single base change
that causes exon skipping in the type I collagen alpha-2(I) chain. Hum.
Genet. 87: 193-198, 1991.

14. Nusgens, B. V.; Verellen-Dumoulin, C.; Hermanns-Le, T.; De Paepe,
A.; Nuytinck, L.; Pierard, G. E.; Lapiere, C. M.: Evidence for a
relationship between Ehlers-Danlos type VII C in humans and bovine
dermatosparaxis. Nature Genet. 1: 214-217, 1992.

15. Steinmann, B.; Rao, V. H.; Gitzelmann, R.: A structurally abnormal
alpha-2(I) collagen chain in a further patient with the Ehlers-Danlos
syndrome type VII. Ann. N.Y. Acad. Sci. 460: 506-509, 1985.

16. Steinmann, B.; Tuderman, L.; Peltonen, L.; Martin, G. R.; McKusick,
V. A.; Prockop, D. J.: Evidence for a structural mutation of procollagen
type I in a patient with the Ehlers-Danlos syndrome type VII. J.
Biol. Chem. 255: 8887-8893, 1980.

17. Viljoen, D.; Goldblatt, J.; Thompson, D.; Beighton, P.: Ehlers-Danlos
syndrome: yet another type? Clin. Genet. 32: 196-201, 1987.

18. Watson, R. B.; Wallis, G. A.; Holmes, D. F.; Viljoen, D.; Byers,
P. H.; Kadler, K. E.: Ehlers Danlos syndrome type VIIB: incomplete
cleavage of abnormal type I procollagen by N-proteinase in vitro results
in the formation of copolymers of collagen and partially cleaved pNcollagen
that are near circular in cross-section. J. Biol. Chem. 267: 9093-9100,
1992.

19. Weil, D.; Bernard, M.; Combates, N.; Wirtz, M. K.; Hollister,
D.; Steinmann, B.; Ramirez, F.: Identification of a mutation that
causes exon skipping during collagen pre-mRNA splicing in an Ehlers-Danlos
syndrome variant. J. Biol. Chem. 263: 8561-8564, 1988.

20. Weil, D.; D'Alessio, M.; Ramirez, F.; de Wet, W.; Cole, W. G.;
Chan, D.; Bateman, J. F.: A base substitution in the exon of a collagen
gene causes alternative splicing and generates a structurally abnormal
polypeptide in a patient with Ehlers-Danlos syndrome type VII. EMBO
J. 8: 1705-1710, 1989.

21. Weil, D.; D'Alessio, M.; Ramirez, F.; Steinmann, B.; Wirtz, M.
K.; Glanville, R. W.; Hollister, D. W.: Temperature-dependent expression
of a collagen splicing defect in the fibroblasts of a patient with
Ehlers-Danlos syndrome type VII. J. Biol. Chem. 264: 16804-16809,
1989.

22. Wirtz, M. K.; Glanville, R. W.; Steinmann, B.; Rao, V. H.; Hollister,
D. W.: Ehlers-Danlos syndrome type VIIB: deletion of 18 amino acids
comprising the N-telopeptide region of a pro-alpha-2(I) chain. J.
Biol. Chem. 262: 16376-16385, 1987.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Short stature, mild to moderate

HEAD AND NECK:
[Face];
Midface hypoplasia

SKELETAL:
Joint laxity, severe;
Recurrent joint subluxation;
Premature osteoarthritis;
Osteopenia;
Fractures;
[Spine];
Kyphosis;
Scoliosis;
[Pelvis];
Congenital bilateral hip dislocation

SKIN, NAILS, HAIR:
[Skin];
Thin, velvety skin;
Hyperextensible skin;
Poor wound healing;
Atrophic scars;
Easy bruisability

NEUROLOGIC:
[Central nervous system];
Hypotonia;
Delayed gross motor development

PRENATAL MANIFESTATIONS:
[Delivery];
Breech presentation

MOLECULAR BASIS:
Caused by mutation in the collagen I, alpha-1 polypeptide gene (COL1A1,
120150.0026);
Caused by mutation in the collagen I, alpha-2 polypeptide gene (COL1A2,
120160.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 6/18/2008
Kelly A. Przylepa - revised: 10/24/2002

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 02/07/2011
ckniffin: 6/18/2008
joanna: 10/24/2002

*FIELD* CN
Cassandra L. Kniffin - updated: 6/18/2008
Victor A. McKusick - updated: 12/11/1997
Victor A. McKusick - updated: 10/3/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 01/13/2011
wwang: 7/7/2008
ckniffin: 7/2/2008
ckniffin: 6/18/2008
carol: 3/15/2007
carol: 12/3/2003
carol: 4/4/2003
kayiaros: 7/13/1999
terry: 5/11/1999
carol: 12/8/1998
dkim: 12/8/1998
terry: 5/29/1998
mark: 12/20/1997
terry: 12/11/1997
jenny: 10/7/1997
terry: 10/3/1997
alopez: 7/7/1997
joanna: 6/20/1997
mimadm: 9/24/1994
carol: 7/29/1994
warfield: 3/28/1994
pfoster: 2/16/1994
carol: 12/22/1993
carol: 7/7/1992

MIM 166200
*RECORD*
*FIELD* NO
166200
*FIELD* TI
#166200 OSTEOGENESIS IMPERFECTA, TYPE I
;;OI, TYPE I; OI1;;
OSTEOGENESIS IMPERFECTA TARDA;;
read moreOSTEOGENESIS IMPERFECTA WITH BLUE SCLERAE
OSTEOPENIC NONFRACTURE SYNDROME, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because the OI type I
phenotype can be produced by mutation in either the COL1A1 gene (120150)
or the COL1A2 gene (120160) and possibly in other genes.

DESCRIPTION

Osteogenesis imperfecta type I is a dominantly inherited, generalized
connective tissue disorder characterized mainly by bone fragility and
blue sclerae. In most cases, 'functional null' alleles of COL1A1 on
chromosome 17 or COL1A2 on chromosome 7 lead to reduced amounts of
normal collagen I.

CLINICAL FEATURES

Osteogenesis imperfecta (see Byers, 1993) is characterized chiefly by
multiple bone fractures, usually resulting from minimal trauma. Affected
individuals have blue sclerae, normal teeth, and normal or near-normal
stature (for growth curves, see Vetter et al., 1992). Fractures are rare
in the neonatal period; fracture tendency is constant from childhood to
puberty, decreases thereafter, and often increases following menopause
in women and after the sixth decade in men. Fractures heal rapidly with
evidence of a good callus formation, and, with good orthopedic care,
without deformity. Hearing loss of conductive or mixed type occurs in
about 50% of families, beginning in the late teens and leading,
gradually, to profound deafness, tinnitus, and vertigo by the end of the
fourth to fifth decade. Additional clinical findings may be thin, easily
bruised skin, moderate joint hypermobility and kyphoscoliosis, hernias,
and arcus senilis. Mitral valve prolapse, aortic valvular insufficiency,
and a slightly larger than normal aortic root diameter have been
identified in some individuals (Hortop et al., 1986), but it is not
clear that these disorders are significantly more frequent than in the
general population.

Radiologically, wormian bones are common but bone morphology is
generally normal at birth, although mild osteopenia and femoral bowing
may be present. Vertebral body morphology in the adult is normal
initially, but often develops the classic 'cod-fish' appearance
(Steinmann et al., 1991).

- EYES

Individuals with OI type I have distinctly blue sclerae which remain
intensely blue throughout life, in contrast to the sclerae in OI type
III and OI type IV which may also be blue at birth and during infancy.
The intensity of the blue fades with time such that these individuals
may have sclerae of normal hue by adolescence and adult life (Sillence
et al., 1993). In a likely heterogeneous group of 16 patients with OI
syndromes, Kaiser-Kupfer et al. (1981) found low ocular rigidity and
small corneal diameter and globe length; no correlation was found
between rigidity of the eyeball and blueness of the sclera. The central
corneal thickness was found to be significantly lower in 53 patients
with OI than that in 35 patients with otosclerosis and in 35 control
subjects (Pedersen and Bramsen, 1984).

Hartikka et al. (2004) found that patients with COL1A1 mutations more
frequently had blue sclerae than those with COL1A2 mutations. In
addition, patients with COL1A2 mutations tended to be shorter than those
with COL1A1 mutations.

- CARDIOVASCULAR

The prevalence and severity of cardiovascular involvement in OI type I
was determined in a prospective study of patients of all ages (Pyeritz
and Levin, 1981). Mitral valve prolapse occurred in 18% (3 times the
prevalence in unaffected relatives) and rarely progressed to mitral
regurgitation. Mean aortic root diameter was slightly but significantly
increased and was associated with aortic regurgitation in 1 to 2%. No
patient had suffered a dissection. Later, Hortop et al. (1986) studied
109 persons with nonlethal OI from 66 families. They could demonstrate
no definite increase in the frequency of mitral valve prolapse over that
to be expected in any group of persons. Aortic root dilatation was found
by echocardiogram to be present in 8 of 66 persons with OI syndrome;
dilatation was mild and unrelated to age of the patient but was
strikingly aggregated in families. Of 109 persons surveyed, valvular
disease was evident clinically in only 4 persons (aortic regurgitation
in 2, aortic stenosis in one, and mitral valve prolapse in one). Hortop
et al. (1986) stated that aortic root dilatation was seen in each of the
different OI syndromes but strikingly segregated within certain
families. They concluded that the mild and apparently nonprogressive
nature of this lesion in OI argues against the use of beta-adrenergic
blockade in affected individuals in the absence of systemic arterial
hypertension.

Mayer et al. (1996) reported a 35-year-old woman with a mild form of OI1
who presented with spontaneous dissection of the right internal carotid
artery and the right vertebral artery after scuba diving. She had no
obvious head or neck trauma. Other than a history of easy bruising and
bluish sclerae, she had no evidence of a connective tissue disorder.
There had been no bone fractures or dental problems nor was there family
history of vasculopathy. Genetic analysis identified a heterozygous
mutation in the COL1A1 gene (G13A; 120150.0052).

- EARS

In likely heterogeneous groups of patients with OI, about half of
affected individuals have hearing loss that begins during the second
decade as a conductive loss; older individuals have sensorineural losses
(Riedner et al., 1980; Pedersen, 1984). In only 1 major study was a
majority of patients with sensorineural pattern observed (Shapiro et
al., 1982). A female-to-male preponderance of 2:1 has been reported
(Shea and Postma, 1982). Hearing loss is different from otosclerosis.

Vertigo is frequently associated with otosclerosis in which the hearing
loss clinically resembles that in OI. Vertigo is also common in basilar
impression found in up to 25% of adult OI patients. To evaluate the
cause, frequency, and characteristics of vertigo in OI, Kuurila et al.
(2003) studied 42 patients by interview, clinical examination, and
audiologic examination supplemented with electronystagmography (ENG) and
lateral skull radiography. Audiometry showed hearing loss in 25 patients
(59.5%). In 9 patients (21%), abnormal skull base anatomy was found in
the forms of basilar impression, basilar invagination, or both. Vertigo,
mostly of floating or rotational sensation of short duration, was
reported by 22 patients (52.4%). Patients with hearing loss tended to
have more vertigo than patients with normal hearing. Vertigo was not
correlated with type of hearing loss or auditory brain stem response
pathology. ENG was abnormal in 14 patients (33.3%). Kuurila et al.
(2003) concluded that vertigo is common in patients with OI and that in
most cases, it is secondary to inner ear pathology.

Hartikka et al. (2004) reported a correlative analysis between types of
mutation in the COL1A1 and COL1A2 genes and OI-associated hearing loss.
A total of 54 Finnish OI patients with previously diagnosed hearing loss
or age 35 or more years were analyzed for mutations in COL1A1 or COL1A2.
Altogether 49 mutations were identified, of which 41 were novel. No
correlation was found between the mutated gene or mutation type and
hearing pattern. The authors interpreted this to mean that the basis of
hearing loss in OI is complex, and that it is a result of
multifactorial, still unknown genetic effects.

- SKIN

Using a suction-cup technique, Hansen and Jemec (2002) performed
quantitative studies of skin mechanics (elasticity, distensibility, and
hysteresis) in 10 patients with OI, 8 with type I and 2 with type III
(259420), and 24 age-matched controls. Skin elasticity, distensibility,
and hysteresis were significantly decreased in patients versus controls.
OI type I patients had decreased distensibility and hysteresis but
increased elasticity in comparison to the type III patients. The authors
concluded that the skin of patients with OI is more stiff and less
elastic than normal skin. These changes differ from age-related changes,
which have been described as increased distensibility and viscosity
(similar to hysteresis).

- CRANIOFACIAL AND DENTAL

To obtain baseline information on craniofacial development in OI
patients who had not received bisphosphonate treatment, Waltimo-Siren et
al. (2005) used lateral radiographs to analyze the size and form of the
bony structures in heads of 59 consecutive patients with OI types I,
III, or IV (Sillence classification). In OI type I they found linear
measurements that were smaller than normal, indicating a general growth
deficiency, but no remarkable craniofacial deformity. In OI types III
and IV, the growth impairment was pronounced and the craniofacial form
was altered as a result of differential growth deficiency and bending of
the skeletal head structures. They found strong support both for an
abnormally ventral position of the sella region due to bending of the
cranial base and for a closing mandibular growth rotation. Vertical
underdevelopment of the dentoalveolar structures and the condylar
process were identified as the main reasons for the relative mandibular
prognathism in OI. Waltimo-Siren et al. (2005) concluded that facial
growth impairment would probably remain characteristic for many OI
patients despite the widespread intervention with bisphosphonates and
that orthodontic treatment should be further developed.

- CLINICAL VARIABILITY

The disorder may exhibit considerable interfamilial and intrafamilial
variability in the number of fractures and degree of disability. Rowe et
al. (1985) reported a spectrum of disease severity within a 5-generation
family. Those most severely affected exhibited more severe short stature
and a mild degree of scoliosis relative to those who were less severely
affected. Most striking were identical twins, the offspring of a mildly
affected mother. Twin B was born small for gestational age, had had 12
fractures and was 150 cm tall (third centile) at 11 years of age. Her
twin was born appropriate for gestational age and had had only 2
fractures at age 8 and 9 secondary to strenuous exercise; her current
height was 162 cm (50th centile). This family study suggested that the
severity of the disease is roughly correlated with the reduction in
collagen I synthesis.

Willing et al. (1990) described 5 affected individuals of a 3-generation
family with marked clinical variability. They wondered if there might be
subtle biochemical differences between the family members with respect
to the amount of the abnormal pro-alpha-1(I) chains produced or their
intracellular fate, but no differences were observed. They noticed that
the more severely affected family members had children with both mild
and severe phenotypes, while the mildly affected individual had an
offspring with a mild phenotype. This suggested to them that there might
be some other, not identified, factor segregating independently in this
family that acts to modulate the final phenotype.

- CLASSIFICATION

Using clinical, radiographic, and genetic criteria, Sillence et al.
(1979) developed the classification currently in use into types I to IV:
a dominant form with blue sclerae, type I; a dominant form with normal
sclerae, type IV (166220); a perinatally lethal OI syndrome, type II
(166210); and a progressively deforming form with normal sclerae, type
III. The biochemical and linkage studies support the broad validity of
the classification but confirm that it is incomplete. Although
biochemical and genetic studies will provide the basis of the most
rational classification, even such a detailed scheme probably will never
predict correctly the evolution of OI in every affected individual,
because of the still unexplained variability of expression seen in many
families (Byers, 1993).

Bauze et al. (1975) divided their 42 patients with OI into mild,
moderate, and severe groups according to deformity of long bones. None
of the 17 patients in the mild group had scoliosis or white sclerae. The
terms 'congenita' and 'tarda' now have limited usefulness, since they do
not specify the mode of inheritance or basic biochemical defects.

Levin et al. (1980) concluded that dominant type I OI separates clearly
into families in which affected persons have opalescent teeth and those
in which dentinogenesis imperfecta (DGI) is absent. In 5 families, all
members whose teeth were studied radiographically and by scanning
electron microscopy had opalescent teeth. In 2 families the teeth of all
affected persons were normal. Some members of both classes of families
had blue sclerae and others did not. These 2 forms of OI were designated
type IA and IB, depending on the presence or absence, respectively, of
DGI. Paterson et al. (1983) found that patients with associated DGI
(type IA) have more severe disease, with a greater fracture rate and
greater likelihood of growth impairment, than do type IB patients.

Superti-Furga et al. (2007) discussed the 2006 revisions to the Nosology
of Constitutional Disorders of Bone by the Nosology Group of the
International Skeletal Dysplasia Society and provided a comprehensive
table of the new classification scheme.

BIOCHEMICAL FEATURES

Byers (1993) summarized that 'functional null' alleles, i.e., silent
alleles or mutations leading to excluded proteins, are the most common
biochemical and genetic features of OI type I, although structural
mutations in COL1A1 and COL1A2 leading to the synthesis of abnormal
procollagen I can occasionally produce the OI type I phenotype.

Assessing reports of biochemical findings in the OI syndromes is
difficult because the phenotype and genetics generally are not
specified. Most studies deal, no doubt, with heterogeneous groups of
patients. Several forms of OI were among the earliest of the inherited
disorders of collagen biosynthesis and structure to be studied using
cultured dermal fibroblasts from affected individuals (Martin et al.,
1971; Penttinen et al., 1975). Cells cultured from patients who, in
retrospect, would be considered to have OI type I, synthesized less
procollagen I than did controls, but the mechanism by which production
was decreased was not determined. These studies were extended from
culture to tissue.

Francis et al. (1974) concluded that patients with OI and blue sclerae
tend to have a reduced amount of collagen that has normal stability, as
measured by resistance to depolymerization by pronase, heat, or cold
alkali, whereas those with white sclerae have a normal amount of
collagen with reduced stability; they suggested that a defect in
cross-linking of collagen is present in the severe form of the disease.

Sykes et al. (1977) and, in a slightly extended study, Francis et al.
(1981), found an increased ratio of collagen III to I in dermis and
interpreted this as indicating a deficiency of collagen I. In studies of
44 patients with OI, Cetta et al. (1983) found in the largest category,
the mild form, also an increased ratio of collagens III to I in skin
and, in addition, an increased ratio of hydroxylysine diglycoside to
monoglycoside in skin collagen.

Rowe et al. (1981) proposed that an additional criterion for OI type I
is the production of a reduced quantity of collagen I. Among the cases
of osteogenesis imperfecta with reduced synthesis of pro-alpha-1 chains,
considerable heterogeneity is likely to emerge at the level of gene
structure, as in the case of the globin genes in the thalassemias. Barsh
et al. (1982) found that cultured skin fibroblasts from 3 patients
produced half-normal levels of procollagen type I. Furthermore, the OI
cells contained equimolar amounts of pro-alpha-1(I) and pro-alpha-2(I)
chains, which suggested that trimer assembly and secretion were limited
by the level of pro-alpha-1(I) chain synthesis. The 'extra'
pro-alpha-2(I) chain in the OI cells was in a non-disulfide bonded
configuration and apparently contributed to an increased level of
intracellular degradation. The results of Barsh et al. (1982) suggested
that the stoichiometry of the pro-alpha chains in procollagen I is
determined by the conformation of the chains rather than by the ratio in
which they are synthesized, that molecules containing more than a single
pro-alpha-2(I) chain are not assembled, and that the production of
collagen I can be regulated by controlling synthesis of only one of its
subunits.

Rowe et al. (1985) demonstrated that reductions in collagen I production
and in the ratio of alpha-1(I) to alpha-2(I) mRNA are clearly segregated
with affected individuals within the 5 generation family. Rowe et al.
(1985) further suggested that the severity of the disorder is roughly
correlated with the reduction in collagen I synthesis.

Wenstrup et al. (1990) correlated clinical severity in nonlethal
variants of OI with the nature of the alteration in the alpha chains of
procollagen I secreted by cultured fibroblasts. Cells from 40 probands
secreted about half the normal amount of normal procollagen I and no
identifiable abnormal molecules; these patients were generally of normal
stature, rarely had bone deformity or dentinogenesis imperfecta, and had
blue sclerae. Cells from 74 other probands produced and secreted normal
and abnormal procollagen I molecules; these patients were usually short
and had bone deformity and dentinogenesis imperfecta, and many had gray
or blue-gray sclerae. In cells from yet another 18 probands, Wenstrup et
al. (1990) were unable to identify altered procollagen I synthesis or
structure.

Gauba and Hartgerink (2008) reported the design of a novel model system
based upon collagen-like heterotrimers that can mimic the glycine
mutations present in either the alpha-1 or alpha-2 chains of type I
collagen. The design utilized an electrostatic recognition motif in 3
chains that can force the interaction of any 3 peptides, including AAA
(all same), AAB (2 same and 1 different), or ABC (all different) triple
helices. Therefore, the component peptides could be designed in such a
way that glycine mutations were present in zero, 1, 2, or all 3 chains
of the triple helix. They reported collagen mutants containing 1 or 2
glycine substitutions with structures relevant to native forms of OI.
Gauba and Hartgerink (2008) demonstrated the difference in thermal
stability and refolding half-life times between triple helices that vary
only in the frequency of glycine mutations at a particular position.

By differential scanning calorimetry and circular dichroism, Makareeva
et al. (2008) measured and mapped changes in the collagen melting
temperature (delta-T(m)) for 41 different glycine substitutions from 47
OI patients. In contrast to peptides, they found no correlation of
delta-T(m) with the identity of the substituting residue but instead
observed regular variations in delta-T(m) with the substitution location
on different triple helix regions. To relate the delta-T(m) map to
peptide-based stability predictions, the authors extracted the
activation energy of local helix unfolding from the reported peptide
data and constructed the local helix unfolding map and tested it by
measuring the hydrogen-deuterium exchange rate for glycine NH residues
involved in interchain hydrogen bonds. Makareeva et al. (2008)
delineated regional variations in the collagen triple helix stability.
Two large, flexible regions deduced from the delta-T(m) map aligned with
the regions important for collagen fibril assembly and ligand binding.
One of these regions also aligned with a lethal region for Gly
substitutions in the alpha-1(I) chain.

OTHER FEATURES

Dickson et al. (1975) reported a quantitative and qualitative
abnormality of noncollagenous proteins of bone.

Lancaster et al. (1975) found a consistent morphologic abnormality of
cultured skin fibroblasts: irregular packing of aggregated cells and an
irregular tessellated appearance of individual fibroblasts. Boright et
al. (1984) showed that dermal fibroblasts derived from individuals with
OI type I take longer than control cells to reach confluency, have a
lower cell density at stationary phase and have an abnormal cell shape
as judged by the increased ratio of width to length. An increase in
population doubling time of fibroblasts derived from individuals with
the milder form of OI was also observed by Rowe and Shapiro (1982).

INHERITANCE

The mode of inheritance is autosomal dominant. Penetrance of blue
sclerae is 100 percent, while penetrance of hearing loss is clearly
age-dependent (Garretsen and Cremers, 1991). Paternal age effect for
increased risk of new mutations has been documented although it appears
to be considerably lower than, for example, in achondroplasia (100800).
In 10 cases with OI type I presumed to have arisen by new mutation, the
mean paternal age was increased by 2.1 years (Sillence et al., 1979),
whereas in 38 other cases it was significantly increased by 2.9 years
(Carothers et al., 1986).

Blumsohn et al. (2001) confirmed the presence of a small paternal age
effect in apparently sporadic OI. The study evaluated patients born in
England, Wales, and Scotland between 1961 and 1998. For 357 apparently
sporadic cases among 730 eligible cases, the mean age of fathers at the
birth of their children was 0.87 years greater than expected (p = 0.01).
The relative risk was 1.62 for fathers in the highest quintile of
paternal age compared with fathers in the lowest quintile.

MAPPING

In all but 1 of 11 families with OI tarda, Sykes et al. (1986) found
that the disorder segregated with either the COL1A1 locus or the COL1A2
locus. In 1 small family, segregation occurred with both genes, but this
disorder clearly cannot be linked to both; had further meioses been
available, the OI gene would probably have segregated independently of
at least 1 of the 2 loci. Tsipouras (1987), also, concluded that mild OI
is genetically heterogeneous and that 1 or more loci other than COL1A1
and COL1A2 may be involved in the causation of phenotypically
indistinguishable autosomal dominant OI.

Sykes et al. (1990) studied segregation of the COL1A1 and COL1A2 genes
in 38 dominant osteogenesis imperfecta pedigrees. None of the 38
pedigrees showed recombination between the OI gene and both collagen
loci. All 8 pedigrees with OI type IV (166220) segregated with COL1A2.
On the other hand, 17 type I pedigrees segregated with COL1A1 and 7 with
COL1A2. The concordant locus was uncertain in the remaining 6 OI type I
pedigrees. The presence or absence of presenile hearing loss was the
best predictor of the mutant locus in OI type I families, with 13 of the
17 COL1A1 segregants and none of the 7 COL1A2 segregants showing this
feature. By linkage analysis in 7 autosomal dominant osteogenesis
imperfecta families in Italy, Mottes et al. (1990) showed that the
COL1A1 gene was implicated in 2 families and the COL1A2 gene in 1 family
with OI type I. The COL1A2 gene was implicated in 2 families with OI
type IV. In 2 OI type I families, the molecular genetic data were
insufficient for exclusion of one gene.

MOLECULAR GENETICS

Byers (1993) summarized that 'functional null' alleles are the most
common genetic features of OI type I. The mechanism by which the
synthesis of pro-alpha-1(I) chains is decreased remains a difficult
problem to solve. A variety of mutations, such as deletion of an allele,
promoter and enhancer mutations, splicing mutations, premature
termination, as well as other mutations that result in the inability of
pro-alpha-1(I) chains to assemble into molecules, would presumably
result in the same biochemical picture and the same phenotype.

In some individuals, the decreased production of pro-alpha-1(I) chains
by fibroblasts results from about half-normal steady-state levels of the
mRNA (Rowe et al., 1985). Later studies on these cells indicated that
there is a defect in splicing of the pre-mRNA of COL1A1 that prohibits
transport of the product of the mutant allele to the cytoplasm; the
ratio of pro-alpha-1(I) to pro-alpha-2(I) mRNA was 1:1 in the cytoplasm
instead of the normal 2:1, whereas the ratio was 4:1 in the nucleus
instead of the normal 2:1 (Genovese and Rowe, 1987). Furthermore, a
novel species of alpha-1(I) mRNA present in the nuclear compartment was
not collinear with a cDNA probe (Genovese et al., 1989). In another
individual with OI type I, Stover et al. (1993) demonstrated a G-A
transition in the first position of the splice donor site of intron 26
which resulted in inclusion of the entire succeeding intron in the
mature mRNA that accumulated in the nuclear compartment; apparently
because no abnormal pro-alpha-1(I) chains were synthesized from the
mutant allele, the clinical phenotype of this individual was mild. In a
large study, Willing et al. (1992) showed that among 70 individuals with
OI type I 23 from 21 families were heterozygous at the COL1A1
polymorphic MnlI site. As shown by primer extension with
nucleotide-specific chain termination, there was in each case marked
diminution in steady-state mRNA levels from one COL1A1 allele. Loss of
an allele through deletion or rearrangement was not the cause of the
diminished COL1A1 mRNA levels. Only in one family has the causative
mutation been identified; an A-G transition in the obligatory acceptor
splice site of intron 16 resulted in skipping of exon 17 in the mRNA
which represented only 10% of the total COL1A1 mRNA. Further, linkage
studies in 38 additional families have demonstrated no evidence of
deletion of those regions of the COL1A1 gene used for linkage analysis
(Sykes et al., 1986, 1990) and confirmed that most individuals with the
OI type I phenotype have mutations linked to the COL1A1 gene. In some
families, a similar phenotype is thought to result from mutations in the
COL1A2 gene (Sykes et al., 1986, 1990; Wallis et al., 1986), but the
clinical criteria by which the diagnosis of OI type I is made are not
always clear. Willing et al. (1990) described a 5-bp deletion near the
3-prime end of one COL1A1 allele that resulted in a reading frame shift
12 amino acid residues from the normal terminus of the chain and
predicted an extension of 84 amino acid residues beyond the normal
termination site. Although the abnormal mRNA could be translated in
vitro, it proved extremely difficult to identify the abnormal chains in
cells; it appeared that although the mRNA was present in normal amount,
the protein product was unstable. This mutation provides a model of how
many different mutations in the COL1A1 gene could produce the OI type I
phenotype by resulting in the synthesis of half the normal amount of a
functional pro-alpha-1(I) chain.

In an effort to further understand the reasons for diminished COL1A1
transcript levels in OI type I, Willing et al. (1995) investigated
whether mutations involving key regulatory sequences in the COL1A1
promoter, such as the TATAAA and CCAAAT boxes, are responsible for the
reduced levels of mRNA. They used PCR-amplified genomic DNA in
conjunction with denaturing gradient gel electrophoresis and SSCP to
screen the 5-prime untranslated domain, exon 1, and a small portion of
intron 1 of the COL1A1 gene. In addition, direct sequence analysis was
performed on an amplified genomic DNA fragment that included the TATAAA
and CCAAAT boxes. In a survey of 40 unrelated probands with OI type I in
whom no causative mutation was known, Willing et al. (1995) identified
no mutations in the promoter region and there was 'little evidence of
sequence diversity among any of the 40 subjects.'

Although less common than 'functional null' allele mutations, there are
several examples in which the synthesis of abnormal procollagen I
molecules can produce the OI type I phenotype. In one family (Nicholls
et al., 1984), cells cultured from the affected mother and son, but not
those from the normal daughter, synthesized alpha-1(I)-chains bearing a
cysteine residue within the protease-resistant domain of the collagen
molecule, a region from which that residue is normally absent. Although
it was initially thought that the cysteine substitution was at the X or
Y position of the Gly-X-Y repeating unit of the alpha-1(I) chain in the
carboxyl-terminal peptide CB6 (Steinmann et al., 1986), peptide sequence
analysis and sequencing of the cDNA demonstrated that the mutation
resulted in the substitution of a glycine by cysteine in position 1017
in the telopeptide, 3 amino acid residues from the carboxy-terminal to
the end of the triple helix (Cohn et al., 1988; Labhard et al., 1988).

Other substitutions of cysteine for glycine within the triple helical
domain of the alpha-1(I) chain at residue 94 (Starman et al., 1989;
Nicholls et al., 1990; Shapiro et al., 1992; Byers, 1993) also produce
mild forms of OI, perhaps compatible with OI type I (see, e.g.,
120150.0002 and 120500.0038). Byers et al. (1983) described an isolated
patient with a mild to moderate form of OI: blue sclerae, a height of
147 cm, deformity as a consequence of poor orthopedic treatment, and
hearing loss. Her cells synthesized a pro-alpha-2(I) chain in which
approximately 30 amino acid residues were deleted from the
triple-helical domain, in the CB4 peptide, a domain in which
phosphoproteins important to bone calcification may bind and in which
crosslinks may form. Subsequent studies indicated that a point mutation
at the consensus splice-donor site resulted in the skipping of exon 12
(amino acids 91-108) from about half the COL1A2 transcripts (Rowe et
al., 1990). Zhuang et al. (1993) showed that deletion of 19 bp from +4
to +22 of intron 13 of COL1A2 caused skipping of exon 13 in about 88% of
the transcripts, whereas 12% of the transcripts were normally spliced;
procollagen I containing the mutated pro-alpha-2(I) chain had reduced
thermal stability and was only poorly secreted from the cells.

A woman with 'postmenopausal osteoporosis' was reported by Spotila et
al. (1991) to be heterozygous for a serine-to glycine substitution at
position 661 of the alpha-2(I) triple-helical domain. Since her 3 sons,
who inherited the mutation, had experienced fractures as adolescents,
the diagnosis of 'mild OI cannot be fully excluded' according to the
authors' view; one of the sons was homozygous for the mutation due to
partial isodisomy for maternal chromosome 7 (Spotila et al., 1992). All
these findings suggest that other point mutations in the COL1A1 gene,
and perhaps in the COL1A2 gene (as suggested also by linkage studies),
could lead to a phenotype similar to that produced by 'functional null'
allele mutations.

DIAGNOSIS

The diagnosis is based on clinical and genetic criteria. In sporadic
cases, the diagnosis may be difficult, and secondary osteoporosis and
nonaccidental injury has to be ruled out. In women with severe
'postmenopausal osteoporosis' careful clinical investigation and a
thorough personal and family history quite often reveals OI type I.
While the direct molecular characterization is not feasible in the
majority of cases at present, demonstration of reduced synthesis of
procollagen I by dermal fibroblasts is indicative for the disorder.
Lynch et al. (1991) discussed the problem of making the prenatal
diagnosis of OI type I on the basis of linkage.

De Vos et al. (2000) reported the achievement of a normal twin pregnancy
after preimplantation genetic diagnosis for osteogenesis imperfecta type
I. Because 2 blighted ova were seen on ultrasound at 7 weeks' gestation,
the pregnancy was terminated. The female partner with OI type I carried
a 1-bp deletion in exon 43 of the COL1A1 gene, resulting in a premature
stop codon in exon 46. The nonfunctional allele was predicted to result
in the synthesis of too little type I procollagen.

Byers et al. (2006) published practice guidelines for the genetic
evaluation of suspected OI.

CLINICAL MANAGEMENT

Fractures in OI are treated with standard orthopedic procedures
appropriate for the type of fracture and the age, and heal rapidly with
evidence of good callus formation (sometimes with hypertrophic callus
formation) and without deformity. Regular hearing evaluations after
adolescence and early stapedectomy or stapedotomy are recommended. In
postmenopausal women with OI, a long-term physical therapy program to
strengthen the paraspinal muscles, together with estrogen and
progesterone replacement, adequate calcium intake, and perhaps
calcitonin or fluoride administration, may be specifically indicated
(for review, see Steinmann et al., 1990).

Bembi et al. (1997) described the results of treatment of 3 children
with OI type I with cyclic intravenous infusions of
aminohydroxypropylidene bisphosphonate (pamidronate). Each of the
children had repeated bone fractures and low bone density. The rationale
for pamidronate therapy in OI is based on the fact that bisphosphonates
inhibit osteoclastic bone resorption; this leads to increased bone
density and possibly to reduced risk of fracture. Bembi et al. (1997)
reported a clear clinical response over the 22- to 29-month treatments,
with a striking reduction in the frequency of new fractures. They also
observed an effect on bone density. There were no notable adverse
effects during therapy.

In an uncontrolled observational study involving 30 children aged 3 to
16 years with severe osteogenesis imperfecta, Glorieux et al. (1998)
administered pamidronate intravenously at 4- to 6-month intervals for
1.3 to 5.0 years. They observed a sustained reduction in serum alkaline
phosphatase concentrations and in the urinary excretion of calcium and
type I collagen N-telopeptide. Increases in the size of the vertebral
bodies suggested that new bone had formed. The mean incidence of
radiologically confirmed fractures decreased by 1.7 per year (P less
than 0.001). Treatment with pamidronate did not alter the rate of
fracture healing, the growth rate, or the appearance of growth plates.
Mobility and ambulation improved in 16 children and remained unchanged
in the other 14. The children with severe osteogenesis imperfecta
treated by Glorieux et al. (1998) fell into the type III (259420) and
type IV (166220) categories of osteogenesis imperfecta.

Marini (1998) commented that fluoride and calcitonin treatment in OI had
proved unsuccessful. The bisphosphonates are synthetic analogs of
pyrophosphate, a natural inhibitor of osteoclastic bone resorption. They
have been useful in the treatment of osteoporosis, Paget disease of
bone, and fibrous dysplasia.

Lee et al. (2001) performed a prospective open label study to determine
the efficacy and safety of pamidronate in 6 children with OI (3 had OI
type I, 2 had type III, and 1 had type IV). The dose was 1.5 mg/kg
bimonthly over 12 to 23 months. The number of fractures decreased from
median of 3 (range 1-12) to 0 fractures per year (range 0-4) and all
patients experienced improved bone mineral density and decreased serum
alkaline phosphatase.

Astrom and Soderhall (2002) performed a prospective observational study
using disodium pamidronate (APD) in 28 children and adolescents (aged
0.6 to 18 years) with severe OI or a milder form of the disease, but
with spinal compression fractures. All bone metabolism variables in
serum (alkaline phosphatase, osteocalcin, procollagen-1 C-terminal
peptide, collagen-1 teleopeptide) and urine (deoxypyridinoline)
indicated that there was a decrease in bone turnover. All patients
experienced beneficial effects, and the younger patients showed
improvement in well-being, pain, and mobility without significant side
effects. Vertebral remodeling was also seen. They concluded that APD
seemed to be an efficient symptomatic treatment for children and
adolescents with OI.

Lindsay (2002) reviewed the mechanism, effects, risks, and benefits of
bisphosphonate therapy in children with OI. He stated that the clinical
course and attendant morbidity for many children with severe OI is
clearly improved with its judicious use. Nevertheless, since
bisphosphonates accumulate in the bone and residual levels are
measurable after many years, the long-term safety of this approach was
unknown. He recommended that until long-term safety data were available,
pamidronate intervention be reserved for those for whom the benefits
clearly outweighed the risks.

Rauch et al. (2002) compared parameters of iliac bone histomorphometry
in 45 patients (23 girls, 22 boys) with OI types I, III, or IV before
and after 2.4 +/- 0.6 years of treatment with cyclical intravenous
pamidronate (age at the time of the first biopsy, 1.4 to 17.5 years).
There was an increase in bone mass due to increases in cortical width
and trabecular number. The bone surface-based indicators of cancellous
bone remodeling, however, were decreased. There was no evidence of a
mineralization defect in any of the patients.

Rauch et al. (2003) evaluated the effect of intravenous therapy with
pamidronate on bone and mineral metabolism in 165 patients with OI types
I, III, and IV. All patients received intravenous pamidronate infusions
on 3 successive days, administered at age-dependent intervals of 2 to 4
months. During the 3 days of the first infusion cycle, serum
concentrations of ionized calcium dropped and serum PTH levels
transiently almost doubled. Two to 4 months later, ionized calcium had
returned to pretreatment levels. During 4 years of pamidronate therapy,
ionized calcium levels remained stable, but PTH levels increased by
about 30%. Rauch et al. (2003) concluded that serum calcium levels can
decrease considerably during and after pamidronate infusions, requiring
close monitoring especially at the first infusion cycle. In long-term
therapy, bone turnover is suppressed to levels lower than those in
healthy children. The authors stated that the consequences of
chronically low bone turnover in children with OI were unknown.

Zeitlin et al. (2003) analyzed longitudinal growth during cyclical
intravenous pamidronate treatment in children and adolescents (ages 0.04
to 15.6 years at baseline) with moderate to severe forms of OI types I,
III, and IV and found that 4 years of treatment led to a significant
height gain.

Rauch et al. (2006) assessed the effect of long-term pamidronate
treatment on the bone tissue of children and adolescents with OI.
Average areal bone mineral density (aBMD) increased by 72% in the first
half of the observation period, but by only 24% in the second half. Mean
cortical width and cancellous bone volume increased by 87% and 38%,
respectively, between baseline and the first time point during treatment
(P less than 0.001 for all changes). Rauch et al. (2006) concluded that
the gains that can be achieved with pamidronate treatment appear to be
realized largely in the first 2 to 4 years.

Rauch et al. (2006) studied the effect of pamidronate discontinuation in
pediatric patients with moderate to severe OI types I, III, and IV. In
the controlled study, 12 pairs of patients were matched for age, OI
severity, and duration of pamidronate treatment. Pamidronate was stopped
in one patient of each pair; the other continued to receive treatment.
In the observational study, 38 OI patients were examined (mean age, 13.8
years). The intervention was discontinuation of pamidronate treatment
for 2 years. The results indicated that bone mass gains continue after
treatment is stopped, but that lumbar spine aBMD increases less than in
healthy subjects. The size of these effects is growth dependent.

In lethal forms of osteogenesis imperfecta caused by mutation in either
the COL1A1 gene or the COL1A2 gene, the mutations result in the
synthesis of abnormal chains of procollagen that bind to normal chains
synthesized by the same cells and destroy their biologic activity in a
classic dominant-negative manner. Chamberlain et al. (2004) developed a
strategy to inactivate the mutated alleles in cells of the bone marrow
called mesenchymal stem cells (MSCs), or marrow stromal cells. They
chose MSCs because these cells are easily obtained from a patient, they
engraft and differentiate into many tissues after infusion in vivo, and
allogeneic MSCs had produced promising results in a previous trial
involving patients with osteogenesis imperfecta (Prockop et al., 2003;
Horwitz et al., 2002). Chamberlain et al. (2004) designed a gene
construct that targeted exon 1 of the COL1A1 gene. They predicted that,
on insertion, the construct would both inactivate COL1A1 and confer
resistance to the antibiotic neomycin. To insert the gene construct
efficiently into MSCs, they used an adeno-associated virus as a vector.
The results obtained with MSCs from 2 patients with osteogenesis
imperfecta was highly encouraging. In 31 to 90% of the cells that became
resistant to neomycin, the gene construct had inserted itself into
either the wildtype or the mutated COL1A1 allele. In all cultures of the
neomycin-resistant cells, most signs of the dominant-negative protein
defect were corrected--apparently because the cells in which the mutated
allele was inactivated began to produce an adequate amount of wildtype
collagen. Most importantly, the quality of bones synthesized by the
altered MSCs was improved. Prockop (2004) commented on the promising
nature of the approach as well as some of the problems.

POPULATION GENETICS

In the county of Fyn, where approximately 9% of the Danish population
lives, Andersen and Hauge (1989) identified 48 patients with
osteogenesis imperfecta, of whom 17 were born between January 1, 1970
and December 31, 1983. Of the 17, 12 had type I, 2 had type II, 2 had
type III, and 1 had type IV. The point prevalence at birth was
21.8/100,000 and the population prevalence was 10.6/100,000 inhabitants.
All ethnic and racial groups seem to be similarly affected (Byers,
1993).

HISTORY

Kozma (2008) provided a detailed historical review of skeletal
dysplasias in ancient Egypt, with an example of presumed osteogenesis
imperfecta.

ANIMAL MODEL

Bonadio et al. (1990) reported that the heterozygous Mov-13 mouse, which
has a murine retrovirus integrated within the first intron of The Col1a1
gene, is a good model for the mild autosomal dominant form of OI. The
animals showed morphologic and functional defects in mineralized and
nonmineralized connective tissue and progressive hearing loss.

Aihara et al. (2003) demonstrated that mice with a targeted mutation of
the Col1a1 gene had ocular hypertension. They suggested an association
between intraocular pressure regulation and fibrillar collagen turnover.

*FIELD* SA
Beighton (1981); Bierring (1933); Byers et al. (1982); Byers et
al. (1981); Byers et al. (1980); Byers et al. (1991); Castells et
al. (1979); Cetta et al. (1977); Cohn et al. (1986); Delvin et al.
(1979); Francis et al. (1975); Francis and Smith (1975); Heyes et
al. (1960); Levin et al. (1981); Levin et al. (1978); Levin et al.
(1988); Lindberg et al. (1979); Lukinmaa et al. (1987); Muller et
al. (1977); Prockop and Kivirikko (1984); Sauk et al. (1980); Shapiro
et al. (1983); Sillence (1988); Solomons and Styner (1969); Tsipouras
et al. (1984); Tsipouras et al. (1983); Velley (1974); Willing et
al. (1993)
*FIELD* RF
1. Aihara, M.; Lindsey, J. D.; Weinreb, R. N.: Ocular hypertension
in mice with a targeted type I collagen mutation. Invest. Ophthal.
Vis. Sci. 44: 1581-1585, 2003.

2. Andersen, P. E., Jr.; Hauge, M.: Osteogenesis imperfecta: a genetic,
radiological, and epidemiological study. Clin. Genet. 36: 250-255,
1989.

3. Astrom, E.; Soderhall, S.: Beneficial effect of long term intravenous
bisphosphonate treatment of osteogenesis imperfecta. Arch. Dis. Child. 86:
356-364, 2002.

4. Barsh, G. S.; David, K. E.; Byers, P. H.: Type I osteogenesis
imperfecta: a nonfunctional allele for pro-alpha-1(I) chains of type
I procollagen. Proc. Nat. Acad. Sci. 79: 3838-3842, 1982.

5. Bauze, R. J.; Smith, R.; Francis, M. J. O.: A new look at osteogenesis
imperfecta: a clinical, radiological and biochemical study of forty-two
patients. J. Bone Joint Surg. Br. 57: 2-12, 1975.

6. Beighton, P.: Familial dentinogenesis imperfecta, blue sclerae,
and wormian bones without fractures: another type of osteogenesis
imperfecta? J. Med. Genet. 18: 124-128, 1981.

7. Bembi, B.; Parma, A.; Bottega, M.; Ceschel, S.; Zanatta, M.; Martini,
C.; Ciana, G.: Intravenous pamidronate treatment in osteogenesis
imperfecta. J. Pediat. 131: 622-625, 1997.

8. Bierring, K.: Contribution to the perception of osteogenesis imperfecta
congenita and osteopsathyrosis idiopathica as identical disorders. Acta
Chir. Scand. 70: 481-492, 1933.

9. Blumsohn, A.; McAllion, S. J.; Paterson, C. R.: Excess paternal
age in apparently sporadic osteogenesis imperfecta. Am. J. Med. Genet. 100:
280-286, 2001.

10. Bonadio, J.; Saunders, T. L.; Tsai, E.; Goldstein, S. A.; Morris-Wiman,
J.; Brinkley, L.; Dolan, D. F.; Altschuler, R. A.; Hawkins, J. E.,
Jr.; Bateman, J. F.; Mascara, T.; Jaenisch, R.: Transgenic mouse
model of the mild dominant form of osteogenesis imperfecta. Proc.
Nat. Acad. Sci. 87: 7145-7149, 1990.

11. Boright, A. P.; Lancaster, G. A.; Scriver, C. R.: Osteogenesis
imperfecta: a heterogeneous morphologic phenotype in cultured dermal
fibroblasts. Hum. Genet. 67: 29-33, 1984.

12. Byers, P. H.: Osteogenesis imperfecta.In: Royce, P. M.; Steinmann,
B.: Connective Tissue and Its Heritable Disorders: Molecular, Genetic,
and Medical Aspects. New York: Wiley-Liss (pub.) 1993. Pp. 317-350.

13. Byers, P. H.; Barsh, G. S.; Holbrook, K. A.: Molecular pathology
in inherited disorders of collagen metabolism. Hum. Path. 13: 89-95,
1982.

14. Byers, P. H.; Barsh, G. S.; Peterson, K. E.; Holbrook, K. A.;
Rowe, D. W.: Molecular mechanisms of abnormal bone matrix formation
in osteogenesis imperfecta.In: Veis, A.: The Chemistry and Biology
of Mineralized Connective Tissues. Amsterdam: Elsevier/North Holland
(pub.) 1981.

15. Byers, P. H.; Barsh, G. S.; Rowe, D. W.; Peterson, K. E.; Holbrook,
K. A.; Shapiro, J.: Biochemical heterogeneity in osteogenesis imperfecta.
(Abstract) Am. J. Hum. Genet. 32: 37A only, 1980.

16. Byers, P. H.; Krakow, D.; Nunes, M. E.; Pepin, M.: Genetic evaluation
of suspected osteogenesis imperfecta (OI). Genet. Med. 8: 383-388,
2006.

17. Byers, P. H.; Shapiro, J. R.; Rowe, D. W.; David, K. E.; Holbrook,
K. A.: Abnormal alpha2-chain in type I collagen from a patient with
a form of osteogenesis imperfecta. J. Clin. Invest. 71: 689-697,
1983.

18. Byers, P. H.; Wallis, G. A.; Willing, M. C.: Osteogenesis imperfecta:
translation of mutation to phenotype. J. Med. Genet. 28: 433-442,
1991.

19. Carothers, A. D.; McAllion, S. J.; Paterson, C. R.: Risk of dominant
mutation in older fathers: evidence from osteogenesis imperfecta. J.
Med. Genet. 23: 227-230, 1986.

20. Castells, S.; Colbert, C.; Charkrabarti, C.; Bachtell, R. S.;
Kassner, E. G.; Yasumura, S.: Therapy of osteogenesis imperfecta
with synthetic salmon calcitonin. J. Pediat. 95: 807-811, 1979.

21. Cetta, G.; de Luca, G.; Tenni, R.; Zanaboni, G.; Lenzi, L.; Castellani,
A. A.: Biochemical investigations of different forms of osteogenesis
imperfecta: evaluation of 44 cases. Connect. Tissue Res. 11: 103-111,
1983.

22. Cetta, G.; Lenzi, L.; Rizzotti, M.; Ruggeri, A.; Valli, M.; Boni,
M.: Osteogenesis imperfecta: morphological, histochemical, and biochemical
aspects: modifications induced by (+)-catechin. Connect. Tissue Res. 5:
51-58, 1977.

23. Chamberlain, J. R.; Schwarze, U.; Wang, P.-R.; Hirata, R. K.;
Hankenson, K. D.; Pace, J. M.; Underwood, R. A.; Song, K. M.; Sussman,
M.; Byers, P. H.; Russell, D. W.: Gene targeting in stem cells from
individuals with osteogenesis imperfecta. Science 303: 1198-1201,
2004.

24. Cohn, D. H.; Apone, S.; Eyre, D. R.; Starman, B. J.; Andreassen,
P.; Charbonneau, H.; Nicholls, A. C.; Pope, F. M.; Byers, P. H.:
Substitution of cysteine for glycine within the carboxyl-terminal
telopeptide of the alpha1 chain of type I collagen produces mild osteogenesis
imperfecta. J. Biol. Chem. 263: 14605-14607, 1988.

25. Cohn, D. H.; Byers, P. H.; Steinmann, B.; Gelinas, R. E.: Lethal
osteogenesis imperfecta resulting from a single nucleotide change
in one human pro-alpha-1(I) collagen allele. Proc. Nat. Acad. Sci. 83:
6045-6047, 1986.

26. Delvin, E. E.; Glorieux, F. H.; Lopez, E.: In vitro sulfate turnover
in osteogenesis imperfecta congenita and tarda. Am. J. Med. Genet. 4:
349-355, 1979.

27. De Vos, A.; Sermon, K.; Van de Velde, H.; Joris, H.; Vandervorst,
M.; Lissens, W.; De Paepe, A.; Liebaers, I.; Van Steirteghem, A.:
Two pregnancies after preimplantation genetic diagnosis for osteogenesis
imperfecta type I and type IV. Hum. Genet. 106: 605-613, 2000.

28. Dickson, I. R.; Millar, E. A.; Veis, A.: Evidence for abnormality
of bone-matrix proteins in osteogenesis imperfecta. Lancet 306:
586-587, 1975. Note: Originally Volume II.

29. Francis, M. J. O.; Bauze, R. J.; Smith, R.: Osteogenesis imperfecta:
a new classification. Birth Defects Orig. Art. Ser. XI(6): 99-102,
1975.

30. Francis, M. J. O.; Smith, R.: Polymeric collagen of skin in osteogenesis
imperfecta, homocystinuria, Ehlers-Danlos and Marfan syndromes. Birth
Defects Orig. Art. Ser. XI(6): 15-21, 1975.

31. Francis, M. J. O.; Smith, R.; Bauze, R. J.: Instability of polymeric
skin collagen in osteogenesis imperfecta. Brit. Med. J. 1: 421-424,
1974.

32. Francis, M. J. O.; Williams, K. J.; Sykes, B. C.; Smith, R.:
The relative amounts of the collagen chains alpha-1(I), alpha-2 and
alpha-1(III) in the skin of 31 patients with osteogenesis imperfecta. Clin.
Sci. 60: 617-623, 1981.

33. Garretsen, T. J. T. M.; Cremers, C. W. R. J.: Clinical and genetic
aspects in autosomal dominant inherited osteogenesis imperfecta type
I. Ann. N.Y. Acad. Sci. 630: 240-248, 1991.

34. Gauba, V.; Hartgerink, J. D.: Synthetic collagen heterotrimers:
structural mimics of wild-type and mutant collagen type I. J. Am.
Chem. Soc. 130: 7509-7515, 2008.

35. Genovese, C.; Brufsky, A.; Shapiro, J.; Rowe, D.: Detection of
mutations in human type I collagen mRNA in osteogenesis imperfecta
by indirect RNase protection. J. Biol. Chem. 264: 9632-9637, 1989.

36. Genovese, C.; Rowe, D.: Analysis of cytoplasmatic and nuclear
messenger RNA in fibroblasts from patients with type I osteogenesis
imperfecta. Methods Enzymol. 145: 223-235, 1987.

37. Glorieux, F. H.; Bishop, N. J.; Plotkin, H.; Chabot, G.; Lanoue,
G.; Travers, R.: Cyclic administration of pamidronate in children
with severe osteogenesis imperfecta. New Eng. J. Med. 339: 947-952,
1998.

38. Hansen, B.; Jemec, G. B. E.: The mechanical properties of skin
in osteogenesis imperfecta. Arch. Derm. 138: 909-911, 2002.

39. Hartikka, H.; Kuurila, K.; Korkko, J.; Kaitila, I.; Grenman, R.;
Pynnonen, S.; Hyland, J. C.; Ala-Kokko, L.: Lack of correlation between
the type of COL1A1 or COL1A2 mutation and hearing loss in osteogenesis
imperfecta patients. Hum. Mutat. 24: 147-154, 2004. Note: Erratum:
Hum. Mutat. 24: 437 only, 2004.

40. Heyes, F. M.; Blattner, R. J.; Robinson, H. B. G.: Osteogenesis
imperfecta and odontogenesis imperfecta: clinical and genetic aspects
in eighteen families. J. Pediat. 56: 235-245, 1960.

41. Hortop, J.; Tsipouras, P.; Hanley, J. A.; Maron, B. J.; Shapiro,
J. R.: Cardiovascular involvement in osteogenesis imperfecta. Circulation 73:
54-61, 1986.

42. Horwitz, E. M.; Gordon, P. L.; Koo, W. K. K.; Marx, J. C.; Neel,
M. D.; McNall, R. Y.; Muul, L.; Hofmann, T.: Isolated allogeneic
bone marrow-derived mesenchymal cells engraft and stimulate growth
in children with osteogenesis imperfecta: implications for cell therapy
of bone. Proc. Nat. Acad. Sci. 99: 8932-8937, 2002.

43. Kaiser-Kupfer, M. I.; McCain, L.; Shapiro, J. R.; Podgor, M. J.;
Kupfer, C.; Rowe, D.: Low ocular rigidity in patients with osteogenesis
imperfecta. Invest. Ophthal. 20: 807-809, 1981.

44. Kozma, C.: Skeletal dysplasia in ancient Egypt. Am. J. Med.
Genet. 146A: 3104-3112, 2008.

45. Kuurila, K.; Kentala, E.; Karjalainen, S.; Pynnonen, S.; Kovero,
O.; Kaitila, I.; Grenman, R.; Waltimo, J.: Vestibular dysfunction
in adult patients with osteogenesis imperfecta. Am. J. Med. Genet. 120A:
350-358, 2003.

46. Labhard, M. E.; Wirtz, M. K.; Pope, F. M.; Nicholls, A. C.; Hollister,
D. W.: A cysteine for glycine substitution at position 1017 in an
alpha-1(I) chain of type I collagen in a patient with mild dominantly
inherited osteogenesis imperfecta. Molec. Biol. Med. 5: 197-207,
1988.

47. Lancaster, G.; Goldman, H.; Scriver, C. R.; Gold, R. J. M.; Wong,
I.: Dominantly inherited osteogenesis imperfecta in man: an examination
of collagen biosynthesis. Pediat. Res. 9: 83-88, 1975.

48. Lee, Y.-S.; Low, S.-L.; Lim, L.-A.; Loke, K.-Y.: Cyclic pamidronate
infusion improves bone mineralisation and reduces fracture incidence
in osteogenesis imperfecta. Europ. J. Pediat. 160: 641-644, 2001.

49. Levin, L. S.; Brady, J. M.; Melnick, M.: Scanning electron microscopy
of teeth in dominant osteogenesis imperfecta. Am. J. Med. Genet. 5:
189-199, 1980.

50. Levin, L. S.; Pyeritz, R. E.; Young, R. J.; Holliday, M. J.; Laspia,
C. C.: Dominant osteogenesis imperfecta: heterogeneity and variation
in expression. (Abstract) Am. J. Hum. Genet. 33: 66A only, 1981.

51. Levin, L. S.; Salinas, C. F.; Jorgenson, R. J.: Classification
of osteogenesis imperfecta by dental characteristics. (Letter) Lancet 311:
332-333, 1978. Note: Originally Volume I.

52. Levin, L. S.; Young, R. J.; Pyeritz, R. E.: Osteogenesis imperfecta
type I with unusual dental abnormalities. Am. J. Med. Genet. 31:
921-932, 1988.

53. Lindberg, K. A.; Sivarajah, A.; Murad, S.; Pinnell, S. R.: Abnormal
collagen crosslinks in a family with osteogenesis imperfecta. (Abstract) Clin.
Res. 27: 243A only, 1979.

54. Lindsay, R.: Modeling the benefits of pamidronate in children
with osteogenesis imperfecta. J. Clin. Invest. 110: 1239-1241, 2002.

55. Lukinmaa, P.-L.; Ranta, H.; Ranta, K.; Kaitila, I.: Dental findings
in osteogenesis imperfecta: I. Occurrence and expression of type I
dentinogenesis imperfecta. J. Craniofac. Genet. 7: 115-125, 1987.

56. Lynch, J. R.; Ogilvie, D.; Priestley, L.; Baigrie, C.; Smith,
R.; Farndon, P.; Sykes, B.: Prenatal diagnosis of osteogenesis imperfecta
by identification of the concordant collagen 1 allele. J. Med. Genet. 28:
145-150, 1991.

57. Makareeva, E.; Mertz, E. L.; Kuznetsova, N. V.; Sutter, M. B.;
DeRidder, A. M.; Cabral, W. A.; Barnes, A. M.; McBride, D. J.; Marini,
J. C.; Leikin, S.: Structural heterogeneity of type I collagen triple
helix and its role in osteogenesis imperfecta. J. Biol. Chem. 283:
4787-4798, 2008.

58. Marini, J. C.: Osteogenesis imperfecta--managing brittle bones.
(Editorial) New Eng. J. Med. 339: 986-987, 1998.

59. Martin, G. R.; Layman, D. L.; Narayanan, A. S.; Nigra, T. P.;
Siegel, R. C.: Collagen synthesis by cultured human fibroblasts.
(Abstract) Isr. J. Med. Sci. 7: 455-456, 1971.

60. Mayer, S. A.; Rubin, B. S.; Starman, B. J.; Byers, P. H.: Spontaneous
multivessel cervical artery dissection in a patient with a substitution
of alanine for glycine (G13A) in the alpha-1(I) chain of type I collagen. Neurology 47:
552-556, 1996.

61. Mottes, M.; Cugola, L.; Cappello, N.; Pignatti, P. F.: Segregation
analysis of dominant osteogenesis imperfecta in Italy. J. Med. Genet. 27:
367-370, 1990.

62. Muller, P. K.; Raisch, K.; Matzen, K.; Gay, S.: Presence of type
III collagen in bone from a patient with osteogenesis imperfecta. Europ.
J. Pediat. 125: 29-37, 1977.

63. Nicholls, A. C.; Oliver, J.; Renouf, D.; Pope, F. M.: Type I
collagen mutation in osteogenesis imperfecta and inherited osteoporosis.
(Abstract) 4th Int. Conf. on Osteogenesis Imperfecta, Pavia, Italy 48
only, 9/9/1990.

64. Nicholls, A. C.; Pope, F. M.; Craig, D.: An abnormal collagen
alpha-chain containing cysteine in autosomal dominant osteogenesis
imperfecta. Brit. Med. J. 288: 112-113, 1984.

65. Paterson, C. R.; McAllion, S.; Miller, R.: Heterogeneity of osteogenesis
imperfecta type I. J. Med. Genet. 20: 203-205, 1983.

66. Pedersen, U.: Hearing loss in patients with osteogenesis imperfecta.
A clinical and audiological study of 201 patients. Scand. Audiol. 13:
67-74, 1984.

67. Pedersen, U.; Bramsen, T.: Central corneal thickness in osteogenesis
imperfecta and otosclerosis. O.R.L., J. Otorhinolaryngol. Relat.
Spec. 46: 38-41, 1984.

68. Penttinen, R. P.; Lichtenstein, J. R.; Martin, G. R.; McKusick,
V. A.: Abnormal collagen metabolism in cultured cells in osteogenesis
imperfecta. Proc. Nat. Acad. Sci. 72: 586-589, 1975.

69. Prockop, D. J.: Targeting gene therapy for osteogenesis imperfecta. New
Eng. J. Med. 350: 2302-2304, 2004.

70. Prockop, D. J.; Gregory, C. A.; Spees, J. L.: One strategy for
cell and gene therapy: harnessing the power of adult stem cells to
repair tissues. Proc. Nat. Acad. Sci. 100 (suppl. 1): 11917-11923,
2003.

71. Prockop, D. J.; Kivirikko, K. I.: Heritable diseases of collagen. New
Eng. J. Med. 311: 376-386, 1984.

72. Pyeritz, R. E.; Levin, L. S.: Aortic root dilatation and valvular
dysfunction in osteogenesis imperfecta. (Abstract) Circulation 64:
IV-311 only, 1981.

73. Rauch, F.; Munns, C.; Land, C.; Glorieux, F. H.: Pamidronate
in children and adolescents with osteogenesis imperfecta: effect of
treatment discontinuation. J. Clin. Endocr. Metab. 91: 1268-1274,
2006.

74. Rauch, F.; Plotkin, H.; Travers, R.; Zeitlin, L.; Glorieux, F.
H.: Osteogenesis imperfecta types I, III, and IV: effect of pamidronate
therapy on bone and mineral metabolism. J. Clin. Endocr. Metab. 88:
986-992, 2003.

75. Rauch, F.; Travers, R.; Glorieux, F. H.: Pamidronate in children
with osteogenesis imperfecta: histomorphometric effects of long-term
therapy. J. Clin. Endocr. Metab. 91: 511-516, 2006.

76. Rauch, F.; Travers, R.; Plotkin, H.; Glorieux, F. H.: The effects
of intravenous pamidronate on the bone tissue of children and adolescents
with osteogenesis imperfecta. J. Clin. Invest. 110: 1293-1299, 2002.

77. Riedner, E. D.; Levin, L. S.; Holliday, M. J.: Hearing patterns
in dominant osteogenesis imperfecta. Arch. Otolaryng. 106: 737-740,
1980.

78. Rowe, D. W.; Poirier, M.; Shapiro, J. R.: Type I collagen in
osteogenesis imperfecta: a genetic probe to study type I collagen
biosynthesis.In: Veis, A.: The Chemistry and Biology of Mineralized
Connective Tissues. New York: Elsevier/North Holland (pub.) 1981.
Pp. 155-162.

79. Rowe, D. W.; Shapiro, J. R.: Biochemical features of cultured
skin fibroblasts from patients with osteogenesis imperfecta.In: Akeson,
W. H.; Bornstein, P.; Glimcher, M. J.: Symposium on Heritable Disorders
of Connective Tissue. St. Louis: C. V. Mosby (pub.) 1982. Pp.
269-282.

80. Rowe, D. W.; Shapiro, J. R.; Schlesinger, S.: Diminished type
I collagen synthesis and reduced alpha 1(I) collagen messenger RNA
in cultured fibroblasts from patients with dominantly inherited (type
I) osteogenesis imperfecta. J. Clin. Invest. 76: 604-611, 1985.

81. Rowe, D. W.; Stover, M. L.; McKinstry, M.; Brufsky, A.; Kream,
B.; Chipman, S.; Shapiro, J.: Molecular mechanisms (real and imagined)
for osteopenic bone disease. (Abstract) 4th Int. Conf. on Osteogenesis
Imperfecta, Pavia, Italy 57 only, 9/9/1990.

82. Sauk, J. J.; Gay, R.; Miller, E. J.; Gay, S.: Immunohistochemical
localization of type III collagen in the dentin of patients with osteogenesis
imperfecta and hereditary opalescent dentin. J. Oral Path. 9: 210-220,
1980.

83. Shapiro, J. R.; Pikus, A.; Weiss, G.; Rowe, D. W.: Hearing and
middle ear function in osteogenesis imperfecta. JAMA 247: 2120-2126,
1982.

84. Shapiro, J. R.; Stover, M. L.; Burn, V. E.; McKinstry, M. B.;
Burshell, A. L.; Chipman, S. D.; Rowe, D. W.: An osteopenic nonfracture
syndrome with features of mild osteogenesis imperfecta associated
with the substitution of a cysteine for glycine at triple helix position
43 in the pro-alpha-1(I) chain of type I collagen. J. Clin. Invest. 89:
567-573, 1992.

85. Shapiro, J. R.; Triche, T.; Rowe, D. W.; Munabi, A.; Cattell,
H. S.; Schlesinger, S.: Osteogenesis imperfecta and Paget's disease
of bone. Biochemical and morphological studies. Arch. Intern. Med. 143:
2250-2257, 1983.

86. Shea, J. J.; Postma, D. S.: Findings and long-term surgical results
in the hearing loss of osteogenesis imperfecta. Arch. Otolaryng. 108:
467-470, 1982.

87. Sillence, D.; Butler, B.; Latham, M.; Barlow, K.: Natural history
of blue sclerae in osteogenesis imperfecta. Am. J. Med. Genet. 45:
183-186, 1993.

88. Sillence, D. O.: Osteogenesis imperfecta nosology and genetics. Ann.
N.Y. Acad. Sci. 543: 1-15, 1988.

89. Sillence, D. O.; Senn, A.; Danks, D. M.: Genetic heterogeneity
in osteogenesis imperfecta. J. Med. Genet. 16: 101-116, 1979.

90. Solomons, C. C.; Styner, J.: Osteogenesis imperfecta: effect
of magnesium administration on pyrophosphate metabolism. Calcif.
Tissue Res. 3: 318-326, 1969.

91. Spotila, L. D.; Constantinou, C. D.; Sereda, L.; Ganguly, A.;
Riggs, B. L.; Prockop, D. J.: Mutation in a gene for type I procollagen
(COL1A2) in a woman with postmenopausal osteoporosis: evidence for
phenotypic and genotypic overlap with mild osteogenesis imperfecta. Proc.
Nat. Acad. Sci. 88: 5423-5427, 1991.

92. Spotila, L. D.; Sereda, L.; Prockop, D. J.: Partial isodisomy
for maternal chromosome 7 and short stature in an individual with
a mutation at the COL1A2 locus. Am. J. Hum. Genet. 51: 1396-1405,
1992.

93. Starman, B. J.; Eyre, D.; Charbonneau, H.; Harrylock, M.; Weis,
M. A.; Weiss, L.; Graham, J. M., Jr.; Byers, P. H.: Osteogenesis
imperfecta. The position of substitution for glycine by cysteine in
the triple helical domain of the pro-alpha-1(I) chains of type I collagen
determines the clinical phenotype. J. Clin. Invest. 84: 1206-1214,
1989.

94. Steinmann, B.; Nicholls, A.; Pope, F. M.: Clinical variability
of osteogenesis imperfecta reflecting molecular heterogeneity: cysteine
substitutions in the alpha-1(I) collagen chain producing lethal and
mild forms. J. Biol. Chem. 261: 8958-8964, 1986.

95. Steinmann, B.; Superti-Furga, A.; Giedion, A.: Osteogenesis imperfecta.In:
Dihlmann, W.; Frommhold, W. (eds.): Radiologische Diagnostik in Klinik
und Praxis/Schinz. Vol. 6. Part 2. Stuttgart: Georg Thieme (pub.)
1991. Pp. 728-745.

96. Steinmann, B.; Superti-Furga, A.; Royce, P. M.: Heritable disorders
of connective tissues.In: Fernandes, J.; Saudubray, J.-M.; Tada, K.
: Inborn Metabolic Diseases: Diagnosis and Treatment. Berlin: Springer
(pub.) 1990. Pp. 525-561.

97. Stover, M. L.; Primorac, D.; McKinstry, M. B.; Rowe, D. W.: Defective
splicing of mRNA from one COL1A1 allele of type I collagen in nondeforming
(type I) osteogenesis imperfecta. J. Clin. Invest. 92: 1994-2002,
1993.

98. Superti-Furga, A.; Unger, S.; the Nosology Group of the International
Skeletal Dysplasia Society: Nosology and classification of genetic
skeletal disorders: 2006 revision. Am. J. Med. Genet. 143A: 1-18,
2007.

99. Sykes, B.; Francis, M. J. O.; Phil, F. D.; Smith, R.: Altered
relation of two collagen types in osteogenesis imperfecta. New Eng.
J. Med. 296: 1200-1203, 1977.

100. Sykes, B.; Ogilvie, D.; Wordsworth, P.; Anderson, J.; Jones,
N.: Osteogenesis imperfecta is linked to both type I collagen structural
genes. Lancet 328: 69-72, 1986. Note: Originally Volume II.

101. Sykes, B.; Ogilvie, D.; Wordsworth, P.; Wallis, G.; Mathew, C.;
Beighton, P.; Nicholls, A.; Pope, F. M.; Thompson, E.; Tsipouras,
P.; Schwartz, R.; Jensson, O.; Arnason, A.; Borresen, A.-L.; Heiberg,
A.; Frey, D.; Steinmann, B.: Consistent linkage of dominantly inherited
osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2. Am.
J. Hum. Genet. 46: 293-307, 1990.

102. Tsipouras, P.: Genetic heterogeneity of mild osteogenesis imperfecta
(OI types I and IV): linkage to COL1A1, COL1A2 and possibly other
loci. (Abstract) Cytogenet. Cell Genet. 46: 706 only, 1987.

103. Tsipouras, P.; Borresen, A.; Dickson, L. A.; Berg, K.; Prockop,
D. J.; Ramirez, F.: Molecular heterogeneity in the mild autosomal
dominant forms of osteogenesis imperfecta. Am. J. Hum. Genet. 36:
1172-1179, 1984.

104. Tsipouras, P.; Myers, J. C.; Ramirez, F.; Prockop, D. J.: Restriction
fragment length polymorphism associated with the pro-alpha-2(I) gene
of human type I procollagen: application to a family with an autosomal
dominant form of osteogenesis imperfecta. J. Clin. Invest. 72: 1262-1267,
1983.

105. Velley, J.: Etude clinique et genetique de la dentinogenese
imparfaite hereditaire. Actual Odontostomat. (Paris) 28: 519-532,
1974.

106. Vetter, U.; Pontz, B.; Zauner, E.; Brenner, R. E.; Spranger,
J.: Osteogenesis imperfecta: a clinical study of the first ten years
of life. Calcif. Tissue Int. 50: 36-41, 1992.

107. Wallis, G.; Beighton, P.; Boyd, C.; Mathew, C. G.: Mutations
linked to the pro alpha2(I) collagen gene are responsible for several
cases of osteogenesis imperfecta type I. J. Med. Genet. 23: 411-416,
1986.

108. Waltimo-Siren, J.; Kolkka, M.; Pynnonen, S.; Kuurila, K.; Kaitila,
I.; Kovero, O.: Craniofacial features in osteogenesis imperfecta:
a cephalometric study. Am. J. Med. Genet. 133A: 142-150, 2005.

109. Wenstrup, R. J.; Willing, M. C.; Starman, B. J.; Byers, P. H.
: Distinct biochemical phenotypes predict clinical severity in nonlethal
variants of osteogenesis imperfecta. Am. J. Hum. Genet. 46: 975-982,
1990.

110. Willing, M. C.; Cohn, D. H.; Byers, P. H.: Frameshift mutation
near the 3-prime end of the COL1A1 gene of type I collagen predicts
an elongated pro-alpha-1(I) chain and results in osteogenesis imperfecta
type I. J. Clin. Invest. 85: 282-290, 1990. Note: Erratum: J. Clin.
Invest. 85: following 1338, 1990.

111. Willing, M. C.; Pruchno, C. J.; Atkinson, M.; Byers, P. H.:
Osteogenesis imperfecta type I is commonly due to a COL1A1 null allele
of type I collagen. Am. J. Hum. Genet. 51: 508-515, 1992.

112. Willing, M. C.; Pruchno, C. J.; Byers, P. H.: Molecular heterogeneity
in osteogenesis imperfecta type I. Am. J. Med. Genet. 45: 223-227,
1993.

113. Willing, M. C.; Slayton, R. L.; Pitts, S. H.; Deschenes, S. P.
: Absence of mutations in the promoter of the COL1A1 gene of type
I collagen in patients with osteogenesis imperfecta type I. J. Med.
Genet. 32: 697-700, 1995.

114. Zeitlin, L.; Rauch, F.; Plotkin, H.; Glorieux, F. H.: Height
and weight development during four years of therapy with cyclical
intravenous pamidronate in children and adolescents with osteogenesis
imperfecta types I, III, and IV. Pediatrics 111: 1030-1036, 2003.

115. Zhuang, J.; Tromp, G.; Kuivaniemi, H.; Nakayasu, K.; Prockop,
D. J.: Deletion of 19 base pairs in intron 13 of the gene for the
pro-alpha-2(I) chain of type-I procollagen (COL1A2) causes exon skipping
in a proband with type-I osteogenesis imperfecta. Hum. Genet. 91:
210-216, 1993.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Normal to near normal stature;
Height often shorter than unaffected family members

HEAD AND NECK:
[Ears];
Hearing loss, progressive conductive and/or sensorineural, during
adulthood;
Otosclerosis;
[Eyes];
Blue sclerae;
[Teeth];
Normal teeth (in most patients);
Dentinogenesis imperfecta (rare);
Opalescent teeth (rare)

CARDIOVASCULAR:
[Heart];
Mitral valve prolapse;
[Vessels];
Aortic dilatation (rare);
Spontaneous cervical artery dissection (reported in 1 patient)

SKELETAL:
Mild osteopenia;
Varying degree of multiple fractures;
[Skull];
Wormian bones;
[Spine];
Biconcave flattened vertebrae;
[Limbs];
Occasional femoral bowing;
Mild joint hypermobility

SKIN, NAILS, HAIR:
[Skin];
Thin skin;
Easy bruisability

MISCELLANEOUS:
Onset of fracture usually when child begins to walk;
Fracture frequency constant through childhood, decreases after puberty;
Fractures often heal without deformity;
Fracture frequency increases after menopause and in men ages 60-80

MOLECULAR BASIS:
Caused by mutation in the collagen I, alpha-1 polypeptide gene (COL1A1,
120150.0024)

*FIELD* CN
Joanna S. Amberger - updated: 4/13/2012
Cassandra L. Kniffin - updated: 1/20/2010
Kelly A. Przylepa - revised: 3/13/2000

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 07/23/2013
joanna: 4/13/2012
joanna: 12/6/2011
ckniffin: 1/20/2010
joanna: 6/23/2005
joanna: 10/27/2000
kayiaros: 3/13/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 12/30/2008
Ada Hamosh - updated: 7/9/2008
Marla J. F. O'Neill - updated: 1/2/2008
Ada Hamosh - updated: 7/25/2007
Marla J. F. O'Neill - updated: 6/12/2007
John A. Phillips, III - updated: 5/7/2007
John A. Phillips, III - updated: 3/21/2007
Victor A. McKusick - updated: 3/23/2005
Victor A. McKusick - updated: 9/2/2004
Victor A. McKusick - updated: 6/11/2004
Natalie E. Krasikov - updated: 2/10/2004
John A. Phillips, III - updated: 9/12/2003
Jane Kelly - updated: 8/19/2003
Victor A. McKusick - updated: 8/5/2003
Denise L. M. Goh - updated: 4/1/2003
Denise L. M. Goh - updated: 2/19/2003
Gary A. Bellus - updated: 2/3/2003
Ada Hamosh - updated: 1/30/2002
Sonja A. Rasmussen - updated: 6/8/2001
Victor A. McKusick - updated: 8/16/2000
Victor A. McKusick - updated: 10/2/1998
Moyra Smith - updated: 12/18/1997
Beat Steinmann - updated: 4/18/1994

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
terry: 04/04/2013
terry: 4/4/2013
terry: 6/6/2012
carol: 4/13/2012
terry: 1/13/2011
terry: 10/12/2010
terry: 9/8/2010
terry: 6/3/2010
ckniffin: 1/20/2010
terry: 6/3/2009
terry: 2/4/2009
wwang: 1/7/2009
ckniffin: 12/30/2008
wwang: 7/18/2008
terry: 7/9/2008
carol: 1/2/2008
alopez: 8/2/2007
terry: 7/25/2007
carol: 6/12/2007
carol: 5/7/2007
carol: 3/21/2007
alopez: 3/20/2007
carol: 8/18/2006
carol: 1/13/2006
tkritzer: 3/23/2005
terry: 3/23/2005
alopez: 3/9/2005
terry: 2/14/2005
alopez: 9/5/2004
terry: 9/2/2004
tkritzer: 6/25/2004
terry: 6/11/2004
carol: 2/10/2004
cwells: 9/12/2003
carol: 8/19/2003
tkritzer: 8/6/2003
tkritzer: 8/5/2003
carol: 4/1/2003
carol: 2/19/2003
joanna: 2/12/2003
alopez: 2/3/2003
mgross: 10/7/2002
alopez: 2/4/2002
terry: 1/30/2002
mcapotos: 6/12/2001
mcapotos: 6/8/2001
carol: 8/29/2000
terry: 8/16/2000
terry: 5/20/1999
terry: 5/3/1999
carol: 11/24/1998
carol: 10/7/1998
terry: 10/2/1998
dkim: 7/24/1998
mark: 1/30/1998
alopez: 11/25/1997
alopez: 6/3/1997
joanna: 8/4/1996
mark: 10/22/1995
carol: 1/23/1995
davew: 7/27/1994
terry: 5/3/1994
warfield: 4/21/1994

MIM 166210
*RECORD*
*FIELD* NO
166210
*FIELD* TI
#166210 OSTEOGENESIS IMPERFECTA, TYPE II
;;OI, TYPE II; OI2;;
OSTEOGENESIS IMPERFECTA CONGENITA, PERINATAL LETHAL FORM;;
read moreOSTEOGENESIS IMPERFECTA CONGENITA; OIC;;
VROLIK TYPE OF OSTEOGENESIS IMPERFECTA
*FIELD* TX
A number sign (#) is used with this entry because osteogenesis
imperfecta type II can be caused by heterozygous mutation in the COL1A1
gene (120150) or the COL1A2 gene (120160).

DESCRIPTION

Osteogenesis imperfecta type II constitutes a disorder characterized by
bone fragility, with many perinatal fractures, severe bowing of long
bones, undermineralization, and death in the perinatal period due to
respiratory insufficiency (Sillence et al., 1979; Barnes et al., 2006).

Also see osteogenesis imperfecta type VII (610682), an autosomal
recessive form of lethal OI caused by mutation in the CRTAP gene
(605497).

CLINICAL FEATURES

Morphologically there appear to be 2 forms of OI congenita, a thin-boned
and a broad-boned type. The latter is well illustrated by the male and
female sibs reported by Remigio and Grinvalsky (1970). The diagnosis is
in question, however, because one had dislocated lenses, aortic
coarctation, and basophilic and mucoid changes in the connective tissue
of the heart valves and aorta, while the other had less pronounced
changes of the same nature in the aorta. Parental consanguinity was
denied. Shapiro et al. (1982) suggested that the sibs reported by
Remigio and Grinvalsky (1970) may have had another variant because of
conspicuous extraskeletal features. The broad-bone type is also
illustrated in Figure 8-3 by McKusick (1972) and the thin-bone type in
Figure 8-5. The 'broad-bone' form of osteogenesis imperfecta and type IA
achondrogenesis (200600) bear similarities. In the latter condition the
ribs are thin and prone to fractures but the long bones of the limbs are
severely shortened and bowed.

In a study in Australia, Sillence et al. (1979) encountered a seemingly
recessively inherited lethal perinatal OI with radiologically crumpled
femora and beaded ribs--the 'broad-bone' type.

By scanning electron microscopy, Levin et al. (1982) found no
abnormality of the teeth in a case of OI congenita with death from
pneumonia at age 10 months. Since abnormalities have been described in
reported cases, these results may reflect heterogeneity in OI congenita.
Levin et al. (1982) suggested that the case best fits OI type III of
Sillence et al. (1979). They agreed with Sillence et al. (1979) that the
term 'congenita' has limited usefulness since it merely indicates that
fractures were present at birth--a feature that may occur in type I
(166200), II, or III (259420).

Elejalde and Mercedes de Elejalde (1983) observed a family in which the
fourth child had OIC and died a few hours after birth, and OIC was
diagnosed at 17 weeks' gestation in the fifth pregnancy by
ultrasonography. Diagnosis was based on low echogenic properties of all
bones, abnormally shaped skull and rib cage, distally thinned ribs, and
short, deformed long bones with wide metaphyses and thin diaphyses.

Radiographically the disorder reported by Buyse and Bull (1978) in 3
sibs (see 259410) was indistinguishable from Sillence's group A (see
HISTORY), and chondroosseous histopathology was also identical; however,
low birth weight, microcephaly, and cataracts were also present. The
patients may, of course, have been homozygous for 2 separate but linked
mutations or for a small chromosomal aberration.

Byers et al. (2006) published practice guidelines for the genetic
evaluation of suspected OI.

INHERITANCE

Autosomal recessive inheritance of osteogenesis imperfecta had been
proposed, but in most well-studied cases the diagnosis was found to be
in error or a parent was mosaic for a heterozygous mutation in a
collagen I gene. Smars et al. (1961), McKusick (1962), Awwaad and Reda
(1960), and others described families with 2 or more sibs thought to
have OIC but with ostensibly normal parents. Such is probably to be
expected of a dominant trait with wide expressivity and does not require
a recessive explanation. Hanhart (1951), however, described an inbred
kindred with affected members in 5 sibships. Here germinal mosaicism is
not a satisfactory explanation. In all such studies, care must be taken
not to confuse hypophosphatasia (e.g., 241500) for osteogenesis
imperfecta.

Kaplan and Baldino (1953) described a kindred derived from an inbred,
Arabic-speaking, polygamous sect called the Mozabites, living in
southern Algeria. Nine cases occurred in 4 sibships among the
descendants. Kaplan et al. (1958) and Laplane et al. (1959), in a
follow-up of the same kindred, described 19 cases. Parental
consanguinity was noted by several authors, including Freund and
Lehmacher (1954) and Rohwedder (1953); the latter described a case in
which the parents were brother and sister.

Meyer (1955) reported 'atypical osteogenesis imperfecta' in several of
the 11 offspring of a mentally defective woman by her own father.
Manifestations were spontaneous fractures, generalized osteoporosis, and
Wormian bones in the area of the lambdoidal sutures. Blue sclerae and
deafness were not present.

Young and Harper (1980) concluded that autosomal recessive inheritance
is unlikely to apply to most cases of OIC, including the 'thick boned'
variety. They had information on 79 cases with multiple fractures
present at birth. In only 3 families was more than 1 affected child born
to normal parents and only 1 of the 79 families had consanguineous
parents. The empiric recurrence risk figure is probably closer to 3%
than 25%.

Thompson et al. (1987) thought that recessive inheritance was likely for
Sillence subclassification group B of type II OI (see HISTORY) because
of the frequency of parental consanguinity and multiple affected sibs.
On the other hand, the evidence for dominant inheritance was strong in
the case of group A (Young et al., 1987). Young et al. (1987)
ascertained 30 cases of radiologically proven type II osteogenesis
imperfecta of the Sillence group A subclassification. All were isolated
cases, with 19 unaffected foreborn and 19 unaffected afterborn sibs. Two
sets of parents, both Asian, were consanguineous. Paternal age effect
was observed.

Byers et al. (1988) collected family data and radiographs for 71
probands with the perinatal lethal form of OI and analyzed the collagens
synthesized by dermal fibroblasts cultured from 43 of the probands, 19
parental pairs, and single parents of each of 4 additional probands. In
65 families for which there were complete data, there was recurrence of
OI II in 5 families such that 6 (8.6%) of 70 sibs were affected. In 2
families with recurrence, the radiographic phenotype was milder than
that for the remainder; and 1 of those families was consanguineous,
suggesting autosomal recessive inheritance. In the remaining 3 families
there was no evidence of consanguinity, but in one of them gonadal
mosaicism in the mother was suspected because 3 affected children were
born of 2 different fathers. Biochemical studies indicated that the OI
II phenotype is basically heterogeneous, that most cases result from new
dominant mutations in the genes encoding type I collagen, and that some
recurrences can be accounted for by gonadal mosaicism in one of the
parents.

Daw et al. (1990) reported a remarkable family in which lethal OI of the
thin-boned type occurred in 6 sibs with normal, unrelated parents. Daw
et al. (1990) suggested that this was an instance of gonadal mosaicism
for a dominant mutation.

Bonadio et al. (1990) described an infant apparently homozygous for a
point mutation in the COL1A1 gene (120150.0039), a G-to-A transition at
the +5 position within the spliced donor site of intron 14. In both
parents, who were normal and unrelated, Bonadio et al. (1990) found
absence of the mutation in all cells studied. They found evidence for
uniparental disomy for chromosome 17 (Bonadio, 1990), however. This
mutation, combined with uniparental disomy, may be responsible for the
functionally homozygous state of the mutation in this infant. Bonadio
(1992) had not had an opportunity to study the possibility further.

What one might call pseudorecessive inheritance has been observed in
lethal OI congenita, which, as noted earlier, is almost always a new
autosomal dominant mutation. Cohn et al. (1990) and Edwards et al.
(1992) observed 2 offspring with lethal OI and demonstrated mosaicism in
1 parent. In the first case, the mutation was in the COL1A1 gene
(120150.0016) and the mother had the mosaicism and was mildly affected.
In the second case, the mutation was in the COL1A2 gene (120160.0019)
and it was the father who was mosaic. His only manifestations of OI were
shorter stature than his unaffected male relatives and mild
dentinogenesis imperfecta.

In an investigation of paternal age in 106 cases of nonfamilial
osteogenesis imperfecta compared with matched controls, Orioli et al.
(1995) found only slightly elevated mean paternal age in a South
American collaboration and no increase in an Italian collaboration. This
was in contrast to the findings in 78 achondroplasia (100800) patients,
in which a mean paternal age was greatly increased, and in 64 cases of
thanatophoric dysplasia (see 187600), in which it was less strikingly
elevated.

Cole and Dalgleish (1995) estimated the recurrence rate at 7%, owing to
germline mosaicism in 1 parent.

From molecular genetic studies of 39 cases from a series totaling 65
(40M; 25F), Tsipouras et al. (1985) concluded that most cases of OI II
are the result of new dominant mutation. They observed no parental age
effect.

Horwitz et al. (1985) presented evidence that maternal gonadal mosaicism
was responsible for 3 infants with OI II with 2 different fathers.

BIOCHEMICAL FEATURES

In a deceased 4-day-old infant with OIC, Trelstad et al. (1977) found
that the collagen of bone had twice normal content of hydroxylysine and
cartilage collagen, a 55% increase. The levels of covalently bound
glucose and galactose were proportionately increased. Francis et al.
(1981) found increased ratio of alpha-1(I) to alpha-2(I) and of
alpha-1(III) to alpha-2(I) in both clinically normal parents of a child
with severe OI.

Barsh and Byers (1981) restudied the cultured cells from a multiply
studied patient from the Johns Hopkins Hospital with perinatal lethal
osteogenesis imperfecta. This case was the basis of the report by
Penttinen et al. (1975) which provided evidence that one form of OIC has
a defect in synthesis of type I collagen. The clinical findings in this
case were reported by Heller et al. (1975) and the cultured fibroblasts
were also studied by Delvin et al. (1979), Steinmann et al. (1979), and
Turakainen et al. (1980). Barsh and Byers (1981) found that the cells
produced 2 distinct pro-alpha-1 chains of type I collagen, which were
synthesized at the same rate. Analysis of cyanogen bromide peptides
indicated that the 2 chains differed in their primary structures. Thus,
structural abnormalities of type I procollagen prevented this molecule
from being secreted normally, resulting in an anomalously low ratio of
type I procollagen to other extracellular matrix molecules. In 4
phenotypically identical patients, a defect in secretion of type I
procollagen was demonstrated. Thus, although lethal OI congenita is
probably heterogeneous, one form may be autosomal dominant new
mutational in nature and have a defect in secretion of type I collagen.

Byers et al. (1984) gave an update based on new biochemical information.

MOLECULAR GENETICS

In studies of material from the patient of Penttinen et al. (1975) and
Heller et al. (1975), Williams and Prockop (1983) found deletion of
about 500 bp in the gene for pro-alpha-1(I). See also Chu et al. (1983).
This was probably the first characterization of a collagen gene defect.
The deletion left coding sequences in register on either side. As a
result, the mutant allele was expressed and half the pro-alpha-1 chains
synthesized by fibroblasts were shortened by about 80 amino acids.
Three-fourths of the procollagen trimers synthesized by fibroblasts
contained either 1 or 2 shortened pro-alpha chains. The shortening was
such that the presence of even 1 of the mutant pro-alpha-1 chains in a
procollagen molecule prevented it from folding into a triple-helical
configuration. Trimers containing 1 or 2 mutant pro-alpha-1 chains were
rapidly degraded. Prockop (1984) called this 'protein suicide.' In
further studies Chu et al. (1985) showed that the deletion eliminated 3
exons of the triple helical domain. The termini of the rearrangement
were located within 2 short inverted repeats, suggesting that the
self-complementary nature of these DNA elements favored formation of an
intermediate that was the basis of the deletion. The patient's
fibroblasts contained elevated type III collagen (120180) mRNA. The
severity of the clinical presentation (with avulsion of the head and an
arm during delivery) is explained. A null allele for pro-alpha-2 chains
had much less deleterious effect (de Wet et al., 1983).

Steinmann et al. (1982) and Steinmann et al. (1984) studied material
from a male newborn with the lethal perinatal form of OI (and avulsion
of an arm). The mother had the Marfan syndrome, as did several other
members of the kindred including 2 sibs of the OI proband. The father
was healthy and young. The infant's dermis was thinner and collagen
fibrils were smaller in diameter than normal and fibroblasts showed
dilated endoplasmic reticulum filled with granular material. Cultured
fibroblasts synthesized 2 different species of pro-alpha-1(I) chains in
about equal amounts. One chain was normal; the other contained cysteine
in the triple-helical portion of the COOH-terminal cyanogen bromide
peptide alpha-1(I)CB6. Collagen molecules that contained 2 copies of the
mutant chain formed alpha-1(I)-dimers linked through interchain
disulfide bonds. Molecules containing either 1 or 2 mutant chains were
delayed in secretion and underwent excessive posttranslational
modification with resulting increased lysyl hydroxylation and
hydroxylysyl glycosylation. Delay in triple-helix formation seemed to be
responsible for the increased modification. Neither parent had a
demonstrable abnormality of collagen. The authors suspected a point
mutation with substitution of cysteine for glycine. This may have been
the first known example of a point mutation in a collagen gene
(Steinmann, 1983). The role of the mother's Marfan syndrome is unclear;
the molecular defect underlying the Marfan syndrome in this family had
not been determined and it was not known whether the infant inherited
the Marfan gene from the mother. The triple-helical domain of type I
collagen contains no cysteine. It is made up of repeating triplets of
amino acids Gly-X-Y where X and Y are any amino acid except tryptophan,
tyrosine, and cysteine and most commonly proline and hydroxyproline,
respectively. The fact that type III collagen contains cysteine (and
tyrosine) in its triple-helical domain may indicate that its
substitution for X or Y in type I collagen would not have as disruptive
effects as observed here. In the lethal case thought by Steinmann et al.
(1984) to represent a point mutation, Cohn et al. (1986) indeed found
substitution of cysteine for glycine at position 988 of the
triple-helical portion of half of the alpha-1(I) chains of type I
collagen (120150.0018). The mutation disrupted the (G-X-Y)n pattern
necessary for formation of the triple helix. This experiment of nature
established the minimal mutation capable of producing lethal disease,
and the lethality indicated the selective mechanism for stringent
maintenance of collagen gene structure. A possibly high mutation rate
for the OI II phenotype, which may be at least as frequent as 1 in
60,000 births, can be explained, even if most of them are dominants of
the type described here. The COL1A1 gene may present a large target for
lethal mutations because any change in the first 2 positions of the
repeated GGN-NNN-NNN nucleotide sequence that encodes the triple-helical
tripeptide Gly-X-Y is likely to be lethal if it occurs in the part of
the gene encoding the carboxy-terminal half of the triple helix.

Since the substitution of cysteine for glycine at position 988 of COL1A1
(120150.0018) was in the critical first position of the G-X-Y triplet,
the mutation in the heterozygous state caused a lethal clinical picture.
Sequence data confirmed that the mutation was a single base G-to-T
change (Cohn et al., 1986). Conversely, Steinmann et al. (1986) found
that the substitution of cysteine in the same domain of the alpha-1
chain in another family resulted in mild autosomal dominant OI (166200).
The difference resulted from the fact that the substitution of cysteine
was for X or Y rather than for G in the G-X-Y triplet.

GENOTYPE/PHENOTYPE CORRELATIONS

Bodian et al. (2009) screened DNA samples from 62 unrelated individuals
with the perinatal lethal form of OI and identified COL1A1 or COL1A2
mutations in 59 samples and CRTAP or LEPRE1 (610339) mutations in 3
samples. The authors identified 61 distinct heterozygous mutations in
the COL1A1 and COL1A2 genes, including 5 nonsynonymous rare variants of
unknown significance. Sixty SNPs in the COL1A1 gene (including 17 novel
variants) and 82 SNPs in COL1A2 (including 18 novel variants) were
reported. Their findings suggested a frequency of 5% for CRTAP and
LEPRE1 recessive mutations in severe/lethal OI. A computer model for
predicting the outcome of glycine substitutions within the
triple-helical domain of COL1A1 chains predicted lethality with 90%
accuracy (26 of 29 mutations).

Takagi et al. (2011) studied 4 Japanese patients, including 2 unrelated
patients with what the authors called 'classic OI IIC' (see HISTORY) and
2 sibs with features of 'OI IIC' but less distortion of the tubular
bones (OI dense bone variant). No consanguinity was reported in their
parents. In both sibs and 1 sporadic patient, they identified
heterozygous mutations in the C-propeptide region of COL1A1 (120150.0069
and 120150.0070, respectively), whereas no mutation in this region was
identified in the other sporadic patient. Familial gene analysis
revealed somatic mosaicism of the mutation in the clinically unaffected
father of the sibs, whereas their mother and healthy older sister did
not have the mutation. Histologic examination in the 2 sporadic cases
showed a network of broad, interconnected cartilaginous trabeculae with
thin osseous seams in the metaphyseal spongiosa. Thick, cartilaginous
trabeculae (cartilaginous cores) were also found in the diaphyseal
spongiosa. Chondrocyte columnization appeared somewhat irregular. These
changes differed from the narrow and short metaphyseal trabeculae found
in other lethal or severe cases of OI. Takagi et al. (2011) concluded
that heterozygous C-propeptide mutations in the COL1A1 gene may result
in OI IIC with or without twisting of the long bones and that OI IIC
appears to be inherited as an autosomal dominant trait.

NOMENCLATURE

The autosomal recessive form of lethal OI designated OI VII (610682) had
previously been designated OI IIB (OI2B). For a short time, the
autosomal dominant form of lethal OI (OI II; OI2) was designated OI IIA
(OI2A).

HISTORY

Sillence et al. (1984) reviewed 48 cases of the perinatal lethal form of
OI (OI type II) and subclassified them into 3 categories on the basis of
radiologic features: group A (38 cases)--short, broad, 'crumpled' long
bones, angulation of tibias and continuously beaded ribs; group B (6
cases)--short, broad, crumpled femurs, angulation of tibias but normal
ribs or ribs with incomplete beading; and group C (4 cases)--long, thin,
inadequately modeled long bones with multiple fractures and thin beaded
ribs. Information for segregation analysis was available on 33 families.
Two or more sibs were affected in 6 of the families; 3 of these 6
families were examined by the authors and found to fall into group A, 2
into group B, and 1 into group C. The parents were related in 1 family
of type A and 1 family of type C. Mean paternal age was not increased.
For all these reasons, Sillence et al. (1984) concluded that most cases
of OI II represent an autosomal recessive disorder. There is, however,
clearly an autosomal dominant form as indicated by biochemical evidence
provided by the studies of Barsh and Byers (1981) that there are 2 types
of collagen I alpha-1 chains synthesized by fibroblasts.

Commenting on the paper of Sillence et al. (1984), Spranger (1984)
stated that 'Type IIC poses no major nosologic problems' because of the
radiologic distinctiveness.

On radiographic grounds, Tsipouras et al. (1985) suggested that 5 types
of type II OI could be distinguished. Five patients in 3 families
appeared to have type 5, the least severe form. The parents of these 5
patients were consanguineous, and Tsipouras et al. (1985) suggested that
the inheritance of type 5 may be autosomal recessive.

HETEROGENEITY

Aitchison et al. (1988) studied a child with type II OI of Sillence
subclassification B who was the product of consanguineous Pakistani
parents. A brother and sister of the proband's mother, also the product
of a consanguineous mating, had died with OI in the perinatal period.
The proband was heterozygous for COL1A1 and COL1A2 genotypes, suggesting
that the mutation causing the disease in this child was not at either of
the structural genes for type I collagen.

ANIMAL MODEL

Stacey et al. (1988) reproduced the OI II phenotype in transgenic mice
carrying a mutant alpha-1(I) collagen gene into which specific glycine
substitutions had been engineered. The experiments reproduced the
findings in patients in whom a single point mutation resulted in OIC:
substitution of glycine by arginine at position 391 (Bateman et al.,
1987) or substitution of glycine by cysteine at position 988 (Cohn et
al., 1986). Constantinou et al. (1989) described a lethal variant of OI
in which a G-to-T substitution converted glycine to cysteine at position
904 of the COL1A1 gene. In addition, the proband may have inherited a
second mutation from her asymptomatic mother that produced an
overmodified and thermally unstable species of type I procollagen. Her
mother was somewhat short and had slightly blue sclerae. Lamande et al.
(1989) used the method of Cotton et al. (1988) to identify single base
changes in the subunits of type I collagen in 5 patients with OIC. In 4
cases, the substitution was found in the alpha-1 subunit, and in 1 it
was located in the alpha-2 chain. In all 5 cases, the first glycine in
the amino acid triplet was replaced: gly-973 and gly-1006 to val,
gly-928 to ala, and gly-976 to arg in the alpha-1 chain and gly-865 to
ser in the alpha-2 chain. These mutations emphasize the importance of
the Gly-X-Y repeating amino acid triplet for normal collagen helix
formation and function. The method of Cotton et al. (1988) exploits the
increased chemical modification of cytosines by hydroxylamine and of
thymines by osmium tetroxide, when they are not paired with their
complementary base. The DNA chain is then cleaved at the modified bases
with piperidine. The use of radioactively end-labeled DNA probes allows
the position of the mismatched cytosines and thymines in the probe to be
determined by electrophoresis of the cleavage products. Cole et al.
(1992) described the occurrence of premature birth in OIC due to
precocious rupture of membranes and antepartum hemorrhage.

*FIELD* SA
Bateman et al. (1984); Braga and Passarge (1981); Goldfarb and Ford
(1954); Goldman et al. (1980); Horan and Beighton (1975); Ibsen (1967);
Pihlajaniemi et al. (1984); Schroder (1964); Stephens et al. (1983);
Wilson (1974); Zeitoun et al. (1963)
*FIELD* RF
1. Aitchison, K.; Ogilvie, D.; Honeyman, M.; Thompson, E.; Sykes,
B.: Homozygous osteogenesis imperfecta unlinked to collagen I genes. Hum.
Genet. 78: 233-236, 1988.

2. Awwaad, S.; Reda, M.: Osteogenesis imperfecta: review of literature
and a report on three cases. Arch. Pediat. 77: 280-290, 1960.

3. Barnes, A. M.; Chang, W.; Morello, R.; Cabral, W. A.; Weis, M.;
Eyre, D. R.; Leikin, S.; Makareeva, E.; Kuznetsova, N.; Uveges, T.
E.; Ashok, A.; Flor, A. W.; Mulvihill, J. J.; Wilson, P. L.; Sundaram,
U. T.; Lee, B.; Marini, J. C.: Deficiency of cartilage-associated
protein in recessive lethal osteogenesis imperfecta. New Eng. J.
Med. 355: 2757-2764, 2006.

4. Barsh, G. S.; Byers, P. H.: Reduced secretion of structurally
abnormal type I procollagen in a form of osteogenesis imperfecta. Proc.
Nat. Acad. Sci. 78: 5142-5146, 1981.

5. Bateman, J. F.; Chan, D.; Walker, I. D.; Rogers, J. G.; Cole, W.
G.: Lethal perinatal osteogenesis imperfecta due to the substitution
of arginine for glycine at residue 391 of the alpha-1(I) chain of
type I collagen. J. Biol. Chem. 262: 7021-7027, 1987.

6. Bateman, J. F.; Mascara, T.; Chan, D.; Cole, W. G.: Abnormal type
I collagen metabolism by cultured fibroblasts in lethal perinatal
osteogenesis imperfecta. Biochem. J. 217: 103-115, 1984.

7. Bodian, D. L.; Chan, T.-F.; Poon, A.; Schwarze, U.; Yang, K.; Byers,
P. H.; Kwok, P.-Y.; Klein, T. E.: Mutation and polymorphism spectrum
in osteogenesis imperfecta type II: implications for genotype-phenotype
relationships. Hum. Molec. Genet. 18: 463-471, 2009. Note: Erratum:
Hum. Molec. Genet. 18: 1893-1895, 2009.

8. Bonadio, J.: Personal Communication. Ann Arbor, Mich. 2/7/1992.

9. Bonadio, J.: Personal Communication. Ann Arbor, Mich. 3/1990.

10. Bonadio, J.; Ramirez, F.; Barr, M.: An intron mutation in the
human alpha-1(I) collagen gene alters the efficiency of pre-mRNA splicing
and is associated with osteogenesis imperfecta type II. J. Biol.
Chem. 265: 2262-2268, 1990.

11. Braga, S.; Passarge, E.: Congenital osteogenesis imperfecta in
three sibs. Hum. Genet. 58: 441-443, 1981.

12. Buyse, M.; Bull, M. J.: A syndrome of osteogenesis imperfecta,
microcephaly, and cataracts. Birth Defects Orig. Art. Ser. XIV(6B):
95-98, 1978.

13. Byers, P. H.; Bonadio, J. F.; Steinmann, B.: Osteogenesis imperfecta:
update and perspective. (Editorial) Am. J. Med. Genet. 17: 429-435,
1984.

14. Byers, P. H.; Krakow, D.; Nunes, M. E.; Pepin, M.: Genetic evaluation
of suspected osteogenesis imperfecta (OI). Genet. Med. 8: 383-388,
2006.

15. Byers, P. H.; Tsipouras, P.; Bonadio, J. F.; Starman, B. J.; Schwartz,
R. C.: Perinatal lethal osteogenesis imperfecta (OI type II): a biochemically
heterogeneous disorder usually due to new mutations in the genes for
type I collagen. Am. J. Hum. Genet. 42: 237-248, 1988.

16. Chu, M.-L.; Gargiulo, V.; Williams, C. J.; Ramirez, F.: Multiexon
deletion in an osteogenesis imperfecta variant with increased type
III collagen mRNA. J. Biol. Chem. 260: 691-694, 1985.

17. Chu, M.-L.; Williams, C. J.; Pepe, G.; Hirsch, J. L.; Prockop,
D. J.; Ramirez, F.: Internal deletion in a collagen gene in a perinatal
lethal form of osteogenesis imperfecta. Nature 304: 78-80, 1983.

18. Cohn, D. H.; Byers, P. H.; Steinmann, B.; Gelinas, R. E.: Lethal
osteogenesis imperfecta resulting from a single nucleotide change
in one human pro-alpha-1(I) collagen allele. Proc. Nat. Acad. Sci. 83:
6045-6047, 1986.

19. Cohn, D. H.; Starman, B. J.; Blumberg, B.; Byers, P. H.: Recurrence
of lethal osteogenesis imperfecta due to parental mosaicism for a
dominant mutation in a human type I collagen gene (COL1A1). Am. J.
Hum. Genet. 46: 591-601, 1990.

20. Cole, W. G.; Dalgleish, R.: Perinatal lethal osteogenesis imperfecta. J.
Med. Genet. 32: 284-289, 1995.

21. Cole, W. G.; Patterson, E.; Bonadio, J.; Campbell, P. E.; Fortune,
D. W.: The clinicopathological features of three babies with osteogenesis
imperfecta resulting from the substitution of glycine by valine in
the pro-alpha-1(I) chain of type I procollagen. J. Med. Genet. 29:
112-118, 1992.

22. Constantinou, C. D.; Nielsen, K. B.; Prockop, D. J.: A lethal
variant of osteogenesis imperfecta has a single base mutation that
substitutes cysteine for glycine 904 of the alpha-1(I) chain of type
I procollagen: the asymptomatic mother has an unidentified mutation
producing an overmodified and unstable type I procollagen. J. Clin.
Invest. 83: 574-584, 1989.

23. Cotton, R. G. H.; Rodrigues, N. R.; Campbell, R. D.: Reactivity
of cytosine and thymine in single-base-pair mismatches with hydroxylamine
and osmium tetroxide and its application to the study of mutations. Proc.
Nat. Acad. Sci. 85: 4397-4401, 1988.

24. Daw, S. C. M.; Gibbs, D. A.; Nicholls, A. C.; Hall, E. C.; Siggers,
D. C.; Pope, F. M.: Lethal osteogenesis imperfecta: a family with
6 affected sibs heterozygous for a type I collagen mutation. (Abstract) J.
Med. Genet. 27: 206, 1990.

25. Delvin, E. E.; Glorieux, F. H.; Lopez, E.: In vitro sulfate turnover
in osteogenesis imperfecta congenita and tarda. Am. J. Med. Genet. 4:
349-355, 1979.

26. de Wet, W. J.; Pihlajaniemi, T.; Myers, J. C.; Kelly, T. E.; Prockop,
D. J.: Synthesis of a shortened pro-alpha-2(I) chain and decreased
synthesis of pro-alpha-2(I) chains in a patient with osteogenesis
imperfecta. J. Biol. Chem. 258: 7721-7727, 1983.

27. Edwards, M. J.; Wenstrup, R. J.; Byers, P. H.; Cohn, D. H.: Recurrence
of lethal osteogenesis imperfecta due to parental mosaicism for a
mutation in the COL1A2 gene of type I collagen: the mosaic parent
exhibits phenotypic features of a mild form of the disease. Hum.
Mutat. 1: 47-54, 1992.

28. Elejalde, B. R.; Mercedes de Elejalde, M.: Prenatal diagnosis
of perinatally lethal osteogenesis imperfecta. Am. J. Med. Genet. 14:
353-359, 1983.

29. Francis, M. J. O.; Williams, K. J.; Sykes, B. C.; Smith, R.:
The relative amounts of the collagen chains alpha-1(I), alpha-2 and
alpha-1(III) in the skin of 31 patients with osteogenesis imperfecta. Clin.
Sci. 60: 617-623, 1981.

30. Freund, R.; Lehmacher, K.: Beitrag zur Vererbung der Osteogenesis
imperfecta. Geburtsh. Frauenheilk. 14: 171-177, 1954.

31. Goldfarb, A. A.; Ford, D., Jr.: Osteogenesis imperfecta congenita
in consecutive siblings. J. Pediat. 44: 264-268, 1954.

32. Goldman, A. B.; Davidson, D.; Pavlov, H.; Bullough, P. G.: 'Popcorn'
calcifications: a prognostic sign in osteogenesis imperfecta. Radiology 136:
351-358, 1980.

33. Hanhart, E.: Ueber eine neue Form von Osteopsathyrosis congenita
mit einfach-rezessivem, sowie 4 neue Sippen mit dominantem Erbgang
und die Frage der Vererbung der sog. Osteogenesis imperfecta. Arch.
Klaus Stift. Vererbungsforsch. 26: 426-437, 1951.

34. Heller, R. H.; Winn, K. J.; Heller, R. M.: The prenatal diagnosis
of osteogenesis imperfecta congenita. Am. J. Obstet. Gynec. 121:
572-573, 1975.

35. Horan, F.; Beighton, P.: Autosomal recessive inheritance of osteogenesis
imperfecta. Clin. Genet. 8: 107-111, 1975.

36. Horwitz, A. L.; Lazda, V.; Byers, P. H.: Recurrent type II (lethal)
osteogenesis imperfecta: apparent dominant inheritance. (Abstract) Am.
J. Hum. Genet. 37: A59, 1985.

37. Ibsen, K. H.: Distinct varieties of osteogenesis imperfecta. Clin.
Orthop. 50: 279-290, 1967.

38. Kaplan, M.; Baldino, C.: Dysplasie periostale paraissant familiale
et transmise suivant le mode Mendelien recessif. Arch. Franc. Pediat. 10:
943-950, 1953.

39. Kaplan, M.; Laplane, M. R.; Debray, P.; Lasfargues, G.: Sur l'heredite
de la dysplasie periostale complement a la communication de M. Kaplan
et C. Baldino. Arch. Franc. Pediat. 15: 1097-1101, 1958.

40. Lamande, S. R.; Dahl, H.-H. M.; Cole, W. G.; Bateman, J. F.:
Characterization of point mutations in the collagen COL1A1 and COL1A2
genes causing lethal perinatal osteogenesis imperfecta. J. Biol.
Chem. 264: 15809-15812, 1989.

41. Laplane, M. R.; Lasfargues, G.; Debray, P.: Essai de classification
genetique des osteogeneses imparfaites. Presse Med. 67: 893-895,
1959.

42. Levin, L. S.; Rosenbaum, K. N.; Brady, J. M.; Dorst, J. P.: Osteogenesis
imperfecta lethal in infancy: case report and scanning electron microscopic
studies of the deciduous teeth. Am. J. Med. Genet. 13: 359-368,
1982.

43. McKusick, V. A.: Medical genetics 1961. J. Chronic Dis. 15:
417-572, 1962. Fig. 50.

44. McKusick, V. A.: Heritable Disorders of Connective Tissue.
St. Louis: C. V. Mosby (pub.) (4th ed.): 1972.

45. Meyer, H. J.: Atypical osteogenesis imperfecta: Lobstein's disease. Arch.
Pediat. 72: 182-186, 1955.

46. Orioli, I. M.; Castilla, E. E.; Scarano, G.; Mastroiacovo, P.
: Effect of paternal age in achondroplasia, thanatophoric dysplasia,
and osteogenesis imperfecta. Am. J. Med. Genet. 59: 209-217, 1995.

47. Penttinen, R. P.; Lichtenstein, J. R.; Martin, G. R.; McKusick,
V. A.: Abnormal collagen metabolism in cultured cells in osteogenesis
imperfecta. Proc. Nat. Acad. Sci. 72: 586-589, 1975.

48. Pihlajaniemi, T.; Dickson, L. A.; Pope, F. M.; Korhonen, V. M.;
Nicholls, A.; Prockop, D. J.; Myers, J. C.: Osteogenesis imperfecta:
cloning of a pro-alpha-2(I) collagen gene with a frameshift mutation. J.
Biol. Chem. 259: 12941-12944, 1984.

49. Prockop, D. J.: Osteogenesis imperfecta: phenotypic heterogeneity,
protein suicide, short and long collagen. Am. J. Hum. Genet. 36:
499-505, 1984.

50. Remigio, P. A.; Grinvalsky, H. T.: Osteogenesis imperfecta congenita:
association with conspicuous extraskeletal connective tissue dysplasia. Am.
J. Dis. Child. 119: 524-528, 1970.

51. Rohwedder, H. J.: Ein Beitrag zur Frage des Erbganges der Osteogenesis
imperfecta Vrolik. Arch. Kinderheilk. 147: 256-262, 1953.

52. Schroder, G.: Eine klinisch-erbbiologische Untersuchung des Krankengutes
in Westfalen. Schaetzung der Mutationsraten fuer den Regierungsbezirk
Munster (Westfalen). Z. Menschl. Vererb. Konstitutionsl. 37: 632-676,
1964.

53. Shapiro, J. E.; Phillips, J. A.; Byers, P. H.; Sanders, R.; Holbrook,
K. A.; Levin, L. S.; Dorst, J.; Barsh, G. S.; Peterson, K. E.; Goldstein,
P.: Prenatal diagnosis of lethal perinatal osteogenesis imperfecta
(OI type II). J. Pediat. 101: 127-133, 1982.

54. Sillence, D. O.; Barlow, K. K.; Garber, A. P.; Hall, J. G.; Rimoin,
D. L.: Osteogenesis imperfecta type II: delineation of the phenotype
with reference to genetic heterogeneity. Am. J. Med. Genet. 17:
407-423, 1984.

55. Sillence, D. O.; Senn, A.; Danks, D. M.: Genetic heterogeneity
in osteogenesis imperfecta. J. Med. Genet. 16: 101-116, 1979.

56. Smars, G.; Beckman, L.; Book, J. A.: Osteogenesis imperfecta
and blood groups. Acta Genet. Statist. Med. 11: 133-136, 1961.

57. Spranger, J.: Osteogenesis imperfecta: a pasture for splitters
and lumpers. (Editorial) Am. J. Med. Genet. 17: 425-428, 1984.

58. Stacey, A.; Bateman, J.; Choi, T.; Mascara, T.; Cole, W.; Jaenisch,
R.: Perinatal lethal osteogenesis imperfecta in transgenic mice bearing
an engineered mutant pro-alpha-1(I) collagen gene. Nature 332: 131-136,
1988.

59. Steinmann, B.: Personal Communication. Zurich, Switzerland
12/19/1983.

60. Steinmann, B.; Nicholls, A.; Pope, F. M.: Clinical variability
of osteogenesis imperfecta reflecting molecular heterogeneity: cysteine
substitutions in the alpha-1(I) collagen chain producing lethal and
mild forms. J. Biol. Chem. 261: 8958-8964, 1986.

61. Steinmann, B.; Rao, V. H.; Vogel, A.; Bruckner, P.; Gitzelmann,
R.; Byers, P. H.: Cysteine in the triple-helical domain of one allelic
product of the alpha-1(I) gene of type I collagen produces a lethal
form of osteogenesis imperfecta. J. Biol. Chem. 259: 11129-11138,
1984.

62. Steinmann, B.; Rao, V. H.; Vogel, A.; Gitzelmann, R.; Byers, P.
H.: A new structural mutation in the alpha-1(I) collagen chain from
a patient with type II osteogenesis imperfecta (OI). (Abstract) Europ.
J. Pediat. 139: 317, 1982.

63. Steinmann, B. U.; Martin, G. R.; Baum, B. I.; Crystal, R. G.:
Synthesis and degradation of collagen by skin fibroblasts from controls
and from patients with osteogenesis imperfecta. FEBS Lett. 101:
269-272, 1979.

64. Stephens, J. D.; Filly, R. A.; Callen, P. W.; Golbus, M. S.:
Prenatal diagnosis of osteogenesis imperfecta type II by real-time
ultrasound. Hum. Genet. 64: 191-193, 1983.

65. Takagi, M.; Hori, N.; Chinen, Y.; Kurosawa, K.; Tanaka, Y.; Oku,
K.; Sakata, H.; Fukuzawa, R.; Nishimura, G.; Spranger, J.; Hasegawa,
T.: Heterozygous C-propeptide mutations in COL1A1: osteogenesis imperfecta
type IIC and dense bone variant. Am. J. Med. Genet. 155A: 2269-2273,
2011.

66. Thompson, E. M.; Young, I. D.; Hall, C. M.; Pembrey, M. E.: Recurrence
risks and prognosis in severe sporadic osteogenesis imperfecta. J.
Med. Genet. 24: 390-405, 1987.

67. Trelstad, R. L.; Rubin, D.; Gross, J.: Osteogenesis imperfecta
congenita: evidence for a generalized molecular disorder of collagen. Lab.
Invest. 36: 501-508, 1977.

68. Tsipouras, P.; Bonadio, J. F.; Schwartz, R. C.; Horwitz, A.; Byers,
P. H.: Osteogenesis imperfecta type II is usually due to new dominant
mutations. (Abstract) Am. J. Hum. Genet. 37: A79, 1985.

69. Turakainen, H.; Larjava, H.; Saarni, H.; Penttinen, R.: Synthesis
of hyaluronic acid and collagen in skin fibroblasts cultured from
patients with osteogenesis imperfecta. Biochim. Biophys. Acta 628:
388-397, 1980.

70. Williams, C. J.; Prockop, D. J.: Synthesis and processing of
a type I procollagen containing shortened pro-alpha-1(I) chains by
fibroblasts from a patient with osteogenesis imperfecta. J. Biol.
Chem. 258: 5915-5921, 1983.

71. Wilson, M. G.: Congenital osteogenesis imperfecta.In: Bergsma,
D.: Skeletal Dysplasias. Amsterdam: Excerpta Medica (pub.) 1974.
Pp. 296-298.

72. Young, I. D.; Harper, P. S.: Recurrence risk in osteogenesis
imperfecta congenita. (Letter) Lancet 315: 432 only, 1980. Note:
Originally Volume I.

73. Young, I. D.; Thompson, E. M.; Hall, C. M.; Pembrey, M. E.: Osteogenesis
imperfecta type IIA: evidence for dominant inheritance. J. Med. Genet. 24:
386-389, 1987.

74. Zeitoun, M. M.; Ibrahim, A. H.; Kassem, A. S.: Osteogenesis imperfecta
congenita in dizygotic twins. Arch. Dis. Child. 38: 289-291, 1963.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Short limb dwarfism;
[Weight];
Low birth weight

HEAD AND NECK:
[Eyes];
Blue sclerae;
[Nose];
Beaked nose

CARDIOVASCULAR:
[Heart];
Congestive heart failure

RESPIRATORY:
[Lung];
Pulmonary insufficiency

CHEST:
[Ribs, sternum, clavicles, and scapulae];
Beaded ribs

SKELETAL:
Numerous multiple fractures present at birth;
[Skull];
Wormian bones;
Soft calvaria;
Absent calvarial mineralization;
Large fontanelles;
[Spine];
Platyspondyly;
[Pelvis];
Hips usually flexed and abducted (frog-leg position);
Flattened acetabulae and iliac wings;
[Limbs];
Tibial bowing;
Broad crumpled long bones;
Telescoped femur

SKIN, NAILS, HAIR:
[Skin];
Thin skin

PRENATAL MANIFESTATIONS:
Nonimmune hydrops;
[Delivery];
Premature birth

MISCELLANEOUS:
Perinatal lethal;
Survival greater than one year rare;
Gonadal and somatic mosaicism reported in parent;
Ultrasound detection in second trimester of pregnancy

MOLECULAR BASIS:
Caused by mutation in the collagen I, alpha-1 polypeptide gene (COL1A1,
120150.0001);
Caused by mutation in the collagen I, alpha-2 polypeptide gene (COL1A2,
120160.0007)

*FIELD* CN
Ada Hamosh - reviewed: 4/12/2000
Kelly A. Przylepa - revised: 3/13/2000
John F. Jackson - updated: 11/25/1998

*FIELD* CD
John F. Jackson: 6/16/1995

*FIELD* ED
joanna: 12/05/2011
joanna: 6/23/2005
joanna: 3/14/2005
joanna: 4/12/2000
kayiaros: 3/13/2000
joanna: 11/25/1998

*FIELD* CN
Nara Sobreira - updated: 04/02/2013
George E. Tiller - updated: 7/31/2009
Ada Hamosh - updated: 7/25/2007
Victor A. McKusick - updated: 11/24/1998

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 04/02/2013
terry: 8/31/2012
carol: 10/6/2011
terry: 9/21/2010
carol: 9/21/2010
wwang: 8/13/2009
terry: 7/31/2009
terry: 2/4/2009
alopez: 8/2/2007
terry: 7/25/2007
alopez: 3/19/2007
alopez: 3/16/2007
carol: 7/26/1999
carol: 11/24/1998
terry: 6/4/1996
mark: 5/22/1995
mimadm: 12/2/1994
terry: 7/29/1994
pfoster: 4/25/1994
carol: 6/24/1992
carol: 5/4/1992