RBCC

Full text data of ABCC6

ABCC6 (ARA, MRP6) [Confidence: low (only semi-automatic identification from reviews)]
Multidrug resistance-associated protein 6 (ATP-binding cassette sub-family C member 6; Anthracycline resistance-associated protein; Multi-specific organic anion transporter E; MOAT-E)

UniProt O95255
ID MRP6_HUMAN Reviewed; 1503 AA.
AC O95255; P78420; Q8TCY8; Q9UMZ7;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 24-NOV-2009, sequence version 2.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Multidrug resistance-associated protein 6;
DE AltName: Full=ATP-binding cassette sub-family C member 6;
DE AltName: Full=Anthracycline resistance-associated protein;
DE AltName: Full=Multi-specific organic anion transporter E;
DE Short=MOAT-E;
GN Name=ABCC6; Synonyms=ARA, MRP6;
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] (ISOFORM 1), AND VARIANT VAL-848.
RX PubMed=10424734; DOI=10.1038/sj.bjc.6690527;
RA Belinsky M.G., Kruh G.D.;
RT "MOAT-E (ARA) is a full-length MRP/cMOAT subfamily transporter
RT expressed in kidney and liver.";
RL Br. J. Cancer 80:1342-1349(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS TRP-64 AND
RP VAL-848.
RX PubMed=9892204;
RA Kool M., van der Linden M., de Haas M., Baas F., Borst P.;
RT "Expression of human MRP6, a homologue of the multidrug resistance
RT protein gene MRP1, in tissues and cancer cells.";
RL Cancer Res. 59:175-182(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=11431746; DOI=10.1053/jhep.2001.25545;
RA Lian Z., Liu J., Pan J., Tufan N.L.S., Zhu M., Arbuthnot P., Kew M.,
RA Clayton M.M., Feitelson M.A.;
RT "A cellular gene up-regulated by hepatitis B virus-encoded X antigen
RT promotes hepatocellular growth and survival.";
RL Hepatology 34:146-146(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANTS TRP-64 AND
RP VAL-848.
RX PubMed=10493829; DOI=10.1006/geno.1999.5927;
RA Loftus B.J., Kim U.-J., Sneddon V.P., Kalush F., Brandon R.,
RA Fuhrmann J., Mason T., Crosby M.L., Barnstead M., Cronin L.,
RA Mays A.D., Cao Y., Xu R.X., Kang H.-L., Mitchell S., Eichler E.E.,
RA Harris P.C., Venter J.C., Adams M.D.;
RT "Genome duplications and other features in 12 Mb of DNA sequence from
RT human chromosome 16p and 16q.";
RL Genomics 60:295-308(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Retinoblastoma;
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 [7]
RP FUNCTION, AND CHARACTERIZATION OF VARIANTS PXE PHE-1298; ARG-1302 AND
RP SER-1321.
RX PubMed=11880368; DOI=10.1074/jbc.M110918200;
RA Ilias A., Urban Z., Seidl T.L., Le Saux O., Sinko E., Boyd C.D.,
RA Sarkadi B., Varadi A.;
RT "Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-
RT associated mutants of human ABCC6 (MRP6).";
RL J. Biol. Chem. 277:16860-16867(2002).
RN [8]
RP REVIEW, AND VARIANT PXE PRO-455.
RX PubMed=11427982; DOI=10.1016/S1471-4914(00)01869-4;
RA Uitto J., Pulkkinen L., Ringpfeil F.;
RT "Molecular genetics of pseudoxanthoma elasticum: a metabolic disorder
RT at the environment-genome interface?";
RL Trends Mol. Med. 7:13-17(2001).
RN [9]
RP SUBCELLULAR LOCATION, TOPOLOGY, AND GLYCOSYLATION AT ASN-15.
RX PubMed=12901863; DOI=10.1016/S0006-291X(03)01349-4;
RA Sinko E., Ilias A., Ujhelly O., Homolya L., Scheffer G.L.,
RA Bergen A.A., Sarkadi B., Varadi A.;
RT "Subcellular localization and N-glycosylation of human ABCC6,
RT expressed in MDCKII cells.";
RL Biochem. Biophys. Res. Commun. 308:263-269(2003).
RN [10]
RP SUBCELLULAR LOCATION.
RX PubMed=23625951; DOI=10.1161/CIRCRESAHA.111.300194;
RA Pomozi V., Le Saux O., Brampton C., Apana A., Ilias A., Szeri F.,
RA Martin L., Monostory K., Paku S., Sarkadi B., Szakacs G., Varadi A.;
RT "ABCC6 is a basolateral plasma membrane protein.";
RL Circ. Res. 112:E148-E151(2013).
RN [11]
RP VARIANT GLN-1268.
RX PubMed=10913334; DOI=10.1006/bbrc.2000.3101;
RA Germain D.P., Perdu J., Remones V., Jeunemaitre X.;
RT "Homozygosity for the R1268Q mutation in MRP6, the pseudoxanthoma
RT elasticum gene, is not disease-causing.";
RL Biochem. Biophys. Res. Commun. 274:297-301(2000).
RN [12]
RP VARIANT TRP-64.
RX PubMed=11058917;
RX DOI=10.1002/1098-1004(200011)16:5<449::AID-HUMU24>3.0.CO;2-O;
RA Germain D.P., Perdu J., Remones V., Manzoni K., Jeunemaitre X.;
RT "Identification of two polymorphisms (c189G>C; c190T>C) in exon 2 of
RT the human MRP6 gene (ABCC6) by screening of Pseudoxanthoma elasticum
RT patients: possible sequence correction?";
RL Hum. Mutat. 16:449-449(2000).
RN [13]
RP VARIANT PXE CYS-1339, AND VARIANT GLN-632.
RX PubMed=10954200; DOI=10.1007/s001090000114;
RA Struk B., Cai L., Zaech S., Ji W., Chung J., Lumsden A., Stumm M.,
RA Huber M., Schaen L., Kim C.-A., Goldsmith L.A., Viljoen D.,
RA Figuera L.E., Fuchs W., Munier F., Ramesar R., Hohl D., Richards R.,
RA Neldner K.H., Lindpaintner K.;
RT "Mutations of the gene encoding the transmembrane transporter protein
RT ABC-C6 cause pseudoxanthoma elasticum.";
RL J. Mol. Med. 78:282-286(2000).
RN [14]
RP VARIANTS PXE PRO-1114; GLN-1138 AND TRP-1314, AND VARIANT ALA-614.
RX PubMed=10835642; DOI=10.1038/76102;
RA Le Saux O., Urban Z., Tschuch C., Csiszar K., Bacchelli B.,
RA Quaglino D., Pasquali-Ronchetti I., Pope F.M., Richards A., Terry S.,
RA Bercovitch L., de Paepe A., Boyd C.D.;
RT "Mutations in a gene encoding an ABC transporter cause pseudoxanthoma
RT elasticum.";
RL Nat. Genet. 25:223-227(2000).
RN [15]
RP VARIANT PXE TRP-1138, AND VARIANT GLN-1268.
RX PubMed=10811882; DOI=10.1073/pnas.100041297;
RA Ringpfeil F., Lebwohl M.G., Christiano A.M., Uitto J.;
RT "Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a
RT transmembrane ATP-binding cassette (ABC) transporter.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:6001-6006(2000).
RN [16]
RP VARIANTS PXE LYS-411; GLN-518; SER-568; PRO-673; GLN-765; PRO-1114;
RP TRP-1121; PRO-1138; GLN-1138; ASP-1203; PHE-1298; ILE-1301; ARG-1302;
RP PRO-1303; GLN-1314; TRP-1314; SER-1321; CYS-1339; HIS-1347; ASN-1361
RP AND THR-1424, AND VARIANTS ASP-61; ARG-207; GLY-265; GLU-281; VAL-319;
RP LYS-497; ALA-614; GLN-632; HIS-953; CYS-1241 AND GLN-1268.
RX PubMed=11536079; DOI=10.1086/323704;
RA Le Saux O., Beck K., Sachsinger C., Silvestri C., Treiber C.,
RA Goering H.H.H., Johnson E.W., De Paepe A., Pope F.M.,
RA Pasquali-Ronchetti I., Bercovitch L., Terry S., Boyd C.D.;
RT "A spectrum of ABCC6 mutations is responsible for pseudoxanthoma
RT elasticum.";
RL Am. J. Hum. Genet. 69:749-764(2001).
RN [17]
RP VARIANTS PXE 60-ARG--TYR-62 DEL; ARG-364 AND ARG-1354, AND VARIANT
RP GLY-265.
RX PubMed=11702217; DOI=10.1007/s004390100582;
RA Pulkkinen L., Nakano A., Ringpfeil F., Uitto J.;
RT "Identification of ABCC6 pseudogenes on human chromosome 16p:
RT implications for mutation detection in pseudoxanthoma elasticum.";
RL Hum. Genet. 109:356-365(2001).
RN [18]
RP VARIANTS ALA-614; GLN-632 AND GLN-1268.
RX PubMed=11776382; DOI=10.1007/s100380170003;
RA Wang J., Near S., Young K., Connelly P.W., Hegele R.A.;
RT "ABCC6 gene polymorphism associated with variation in plasma
RT lipoproteins.";
RL J. Hum. Genet. 46:699-705(2001).
RN [19]
RP VARIANT PXE CYS-1459.
RX PubMed=15098239; DOI=10.1002/ajmg.a.20632;
RA Plomp A.S., Hu X., de Jong P.T., Bergen A.A.;
RT "Does autosomal dominant pseudoxanthoma elasticum exist?";
RL Am. J. Med. Genet. A 126:403-412(2004).
RN [20]
RP VARIANTS PXE ARG-364; LYS-411; GLY-440; GLN-518; CYS-600; MET-810;
RP PRO-820; CYS-1114; MET-1130; GLN-1138; CYS-1339; SER-1346 AND
RP LYS-1400.
RX PubMed=15459974; DOI=10.1002/humu.9284;
RA Gheduzzi D., Guidetti R., Anzivino C., Tarugi P., Di Leo E.,
RA Quaglino D., Ronchetti I.P.;
RT "ABCC6 mutations in Italian families affected by pseudoxanthoma
RT elasticum (PXE).";
RL Hum. Mutat. 24:438-439(2004).
RN [21]
RP VARIANTS PXE VAL-74 DEL; 363-GLN--ARG-373 DEL; GLY-391; GLN-518;
RP ASP-766; MET-1130; GLN-1138 HIS-1238; PRO-1335 AND LYS-1400.
RX PubMed=15086542; DOI=10.1111/j.0022-202X.2004.22312.x;
RA Chassaing N., Martin L., Mazereeuw J., Barrie L., Nizard S.,
RA Bonafe J.L., Calvas P., Hovnanian A.;
RT "Novel ABCC6 mutations in pseudoxanthoma elasticum.";
RL J. Invest. Dermatol. 122:608-613(2004).
RN [22]
RP VARIANTS PXE 60-ARG--TYR-62 DEL; GLU-129; ARG-317; ARG-355; ARG-364;
RP ASP-370; GLY-391; GLY-398; HIS-495; GLN-518; SER-551; VAL-594;
RP PRO-677; TRP-760; GLN-765; GLN-807; TRP-807; GLU-1056; PHE-1036 DEL;
RP PHE-1048 DEL; CYS-1114; LEU-1121; GLN-1138; TRP-1138; GLN-1164;
RP CYS-1221; TRP-1235; ARG-1302; PRO-1303; GLN-1314; CYS-1339; LEU-1339
RP AND TRP-1357, AND VARIANTS THR-78; LYS-125; VAL-158; GLY-265; GLU-281;
RP VAL-319; ILE-514; ALA-614; GLN-632; LYS-724; VAL-742; ILE-946;
RP TRP-1064 AND GLN-1268.
RX PubMed=16086317; DOI=10.1002/humu.20206;
RA Miksch S., Lumsden A., Guenther U.P., Foernzler D., Christen-Zach S.,
RA Daugherty C., Ramesar R.K., Lebwohl M., Hohl D., Neldner K.H.,
RA Lindpaintner K., Richards R.I., Struk B.;
RT "Molecular genetics of pseudoxanthoma elasticum: type and frequency of
RT mutations in ABCC6.";
RL Hum. Mutat. 26:235-248(2005).
RN [23]
RP VARIANTS PXE 60-ARG--TYR-62 DEL; ARG-317; ARG-364; TRP-382; GLY-391;
RP ASN-392; HIS-463 HIS-495; GLN-518; PRO-535; SER-568; CYS-600; CYS-663;
RP PRO-698; ASP-699; PRO-726; LYS-751; ARG-755; TRP-760; GLN-765;
RP ASN-777; MET-811; SER-881; ILE-944; THR-950; ARG-992; CYS-1114;
RP MET-1130; ALA-1133; GLN-1138; TRP-1138; THR-1139; GLN-1164; CYS-1221;
RP HIS-1221; ILE-1226; PHE-1298; ARG-1302; PRO-1303; GLN-1314; TRP-1314;
RP GLN-1335; CYS-1339; HIS-1339 AND THR-1342.
RX PubMed=17617515; DOI=10.1136/jmg.2007.051094;
RA Pfendner E.G., Vanakker O.M., Terry S.F., Vourthis S., McAndrew P.E.,
RA McClain M.R., Fratta S., Marais A.S., Hariri S., Coucke P.J.,
RA Ramsay M., Viljoen D., Terry P.F., De Paepe A., Uitto J.,
RA Bercovitch L.G.;
RT "Mutation detection in the ABCC6 gene and genotype-phenotype analysis
RT in a large international case series affected by pseudoxanthoma
RT elasticum.";
RL J. Med. Genet. 44:621-628(2007).
RN [24]
RP VARIANT [LARGE SCALE ANALYSIS] GLN-1268.
RX PubMed=18987736; DOI=10.1038/nature07485;
RA Ley T.J., Mardis E.R., Ding L., Fulton B., McLellan M.D., Chen K.,
RA Dooling D., Dunford-Shore B.H., McGrath S., Hickenbotham M., Cook L.,
RA Abbott R., Larson D.E., Koboldt D.C., Pohl C., Smith S., Hawkins A.,
RA Abbott S., Locke D., Hillier L.W., Miner T., Fulton L., Magrini V.,
RA Wylie T., Glasscock J., Conyers J., Sander N., Shi X., Osborne J.R.,
RA Minx P., Gordon D., Chinwalla A., Zhao Y., Ries R.E., Payton J.E.,
RA Westervelt P., Tomasson M.H., Watson M., Baty J., Ivanovich J.,
RA Heath S., Shannon W.D., Nagarajan R., Walter M.J., Link D.C.,
RA Graubert T.A., DiPersio J.F., Wilson R.K.;
RT "DNA sequencing of a cytogenetically normal acute myeloid leukaemia
RT genome.";
RL Nature 456:66-72(2008).
RN [25]
RP VARIANTS PXE GLN-518; PRO-726; GLN-1138; ARG-1302; PRO-1335 AND
RP CYS-1339, AND VARIANTS THR-78; GLY-265; MET-417; ALA-614; GLN-632;
RP LEU-724; VAL-742; VAL-848 AND ILE-946.
RX PubMed=19339160; DOI=10.1016/j.jdermsci.2009.02.008;
RA Ramsay M., Greenberg T., Lombard Z., Labrum R., Lubbe S., Aron S.,
RA Marais A.S., Terry S., Bercovitch L., Viljoen D.;
RT "Spectrum of genetic variation at the ABCC6 locus in South Africans:
RT Pseudoxanthoma elasticum patients and healthy individuals.";
RL J. Dermatol. Sci. 54:198-204(2009).
RN [26]
RP VARIANTS PXE GLN-765 AND LYS-1406.
RX PubMed=20034067; DOI=10.1002/ajmg.a.33162;
RA Le Boulanger G., Labreze C., Croue A., Schurgers L.J., Chassaing N.,
RA Wittkampf T., Rutsch F., Martin L.;
RT "An unusual severe vascular case of pseudoxanthoma elasticum
RT presenting as generalized arterial calcification of infancy.";
RL Am. J. Med. Genet. A 152:118-123(2010).
RN [27]
RP VARIANTS GACI2 ARG-355; GLY-391; PHE-590; PHE-1036 DEL; CYS-1114;
RP HIS-1221 AND TRP-1314.
RX PubMed=22209248; DOI=10.1016/j.ajhg.2011.11.020;
RA Nitschke Y., Baujat G., Botschen U., Wittkampf T., du Moulin M.,
RA Stella J., Le Merrer M., Guest G., Lambot K.,
RA Tazarourte-Pinturier M.F., Chassaing N., Roche O., Feenstra I.,
RA Loechner K., Deshpande C., Garber S.J., Chikarmane R., Steinmann B.,
RA Shahinyan T., Martorell L., Davies J., Smith W.E., Kahler S.G.,
RA McCulloch M., Wraige E., Loidi L., Hohne W., Martin L., Hadj-Rabia S.,
RA Terkeltaub R., Rutsch F.;
RT "Generalized arterial calcification of infancy and pseudoxanthoma
RT elasticum can be caused by mutations in either ENPP1 or ABCC6.";
RL Am. J. Hum. Genet. 90:25-39(2012).
CC -!- FUNCTION: May participate directly in the active transport of
CC drugs into subcellular organelles or influence drug distribution
CC indirectly. Transports glutathione conjugates as leukotriene-c4
CC (LTC4) and N-ethylmaleimide S-glutathione (NEM-GS).
CC -!- SUBCELLULAR LOCATION: Basolateral cell membrane; Multi-pass
CC membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O95255-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O95255-2; Sequence=VSP_047315, VSP_047316;
CC Note=Gene prediction based on EST data. May be produced at very
CC low levels due to a premature stop codon in the mRNA, leading to
CC nonsense-mediated mRNA decay;
CC -!- TISSUE SPECIFICITY: Expressed in kidney and liver. Very low
CC expression in other tissues.
CC -!- DISEASE: Pseudoxanthoma elasticum (PXE) [MIM:264800]: A
CC multisystem disorder characterized by accumulation of mineralized
CC and fragmented elastic fibers in the skin, vascular walls, and
CC Burch membrane in the eye. Clinically, patients exhibit
CC characteristic lesions of the posterior segment of the eye
CC including peau d'orange, angioid streaks, and choroidal
CC neovascularizations, of the skin including soft, ivory colored
CC papules in a reticular pattern that predominantly affect the neck
CC and large flexor surfaces, and of the cardiovascular system with
CC peripheral and coronary arterial occlusive disease as well as
CC gastrointestinal bleedings. Note=The disease is caused by
CC mutations affecting the gene represented in this entry. Homozygous
CC or compound heterozygous ABCC6 mutations have been found in the
CC overwhelming majority of cases. Individuals carrying heterozygous
CC mutations express limited manifestations of the pseudoxanthoma
CC elasticum phenotype.
CC -!- DISEASE: Arterial calcification of infancy, generalized, 2 (GACI2)
CC [MIM:614473]: A severe autosomal recessive disorder characterized
CC by calcification of the internal elastic lamina of muscular
CC arteries and stenosis due to myointimal proliferation. The
CC disorder is often fatal within the first 6 months of life because
CC of myocardial ischemia resulting in refractory heart failure.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCC
CC family. Conjugate transporter (TC 3.A.1.208) subfamily.
CC -!- SIMILARITY: Contains 2 ABC transmembrane type-1 domains.
CC -!- SIMILARITY: Contains 2 ABC transporter domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC15785.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Mutations of the ABCC6 gene; Note=Retina
CC International's Scientific Newsletter;
CC URL="http://www.retina-international.org/files/sci-news/abcc6mut.htm";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ABCC6";
CC -!- WEB RESOURCE: Name=ABCMdb; Note=Database for mutations in ABC
CC proteins;
CC URL="http://abcmutations.hegelab.org/proteinDetails?uniprot_id=O95255";
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DR EMBL; AF168791; AAD51293.1; -; mRNA.
DR EMBL; AF076622; AAC79696.1; -; mRNA.
DR EMBL; AY078405; AAL83711.1; -; mRNA.
DR EMBL; U91318; AAC15785.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AC136624; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC050733; AAH50733.1; -; mRNA.
DR RefSeq; NP_001072996.1; NM_001079528.3.
DR RefSeq; NP_001162.4; NM_001171.5.
DR UniGene; Hs.442182; -.
DR ProteinModelPortal; O95255; -.
DR SMR; O95255; 316-847, 1015-1503.
DR IntAct; O95255; 5.
DR STRING; 9606.ENSP00000205557; -.
DR ChEMBL; CHEMBL2073661; -.
DR TCDB; 3.A.1.208.10; the atp-binding cassette (abc) superfamily.
DR PhosphoSite; O95255; -.
DR PaxDb; O95255; -.
DR PRIDE; O95255; -.
DR Ensembl; ENST00000205557; ENSP00000205557; ENSG00000091262.
DR Ensembl; ENST00000575728; ENSP00000461686; ENSG00000091262.
DR GeneID; 368; -.
DR KEGG; hsa:368; -.
DR UCSC; uc002den.4; human.
DR CTD; 368; -.
DR GeneCards; GC16M016243; -.
DR H-InvDB; HIX0026937; -.
DR H-InvDB; HIX0038600; -.
DR HGNC; HGNC:57; ABCC6.
DR MIM; 264800; phenotype.
DR MIM; 603234; gene.
DR MIM; 614473; phenotype.
DR neXtProt; NX_O95255; -.
DR Orphanet; 51608; Generalized arterial calcification of infancy.
DR Orphanet; 758; Pseudoxanthoma elasticum.
DR PharmGKB; PA58; -.
DR eggNOG; COG1132; -.
DR HOVERGEN; HBG108314; -.
DR InParanoid; O95255; -.
DR KO; K05669; -.
DR OMA; HPTVWLT; -.
DR OrthoDB; EOG7MWGW0; -.
DR PhylomeDB; O95255; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR ChiTaRS; ABCC6; human.
DR GeneWiki; ABCC6; -.
DR GenomeRNAi; 368; -.
DR NextBio; 1537; -.
DR PRO; PR:O95255; -.
DR ArrayExpress; O95255; -.
DR Bgee; O95255; -.
DR CleanEx; HS_ABCC6; -.
DR Genevestigator; O95255; -.
DR GO; GO:0016324; C:apical plasma membrane; IEA:Ensembl.
DR GO; GO:0016323; C:basolateral plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0016328; C:lateral plasma membrane; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; TAS:ProtInc.
DR GO; GO:0042626; F:ATPase activity, coupled to transmembrane movement of substances; TAS:ProtInc.
DR GO; GO:0042493; P:response to drug; TAS:ProtInc.
DR GO; GO:0007601; P:visual perception; IEA:UniProtKB-KW.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR011527; ABC1_TM_dom.
DR InterPro; IPR003439; ABC_transporter-like.
DR InterPro; IPR017871; ABC_transporter_CS.
DR InterPro; IPR001140; ABC_transptr_TM_dom.
DR InterPro; IPR005292; Multidrug-R_assoc.
DR InterPro; IPR027417; P-loop_NTPase.
DR Pfam; PF00664; ABC_membrane; 2.
DR Pfam; PF00005; ABC_tran; 2.
DR SMART; SM00382; AAA; 2.
DR SUPFAM; SSF52540; SSF52540; 2.
DR SUPFAM; SSF90123; SSF90123; 2.
DR TIGRFAMs; TIGR00957; MRP_assoc_pro; 1.
DR PROSITE; PS50929; ABC_TM1F; 2.
DR PROSITE; PS00211; ABC_TRANSPORTER_1; 2.
DR PROSITE; PS50893; ABC_TRANSPORTER_2; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Cell membrane; Complete proteome;
KW Disease mutation; Glycoprotein; Membrane; Nucleotide-binding;
KW Polymorphism; Reference proteome; Repeat; Sensory transduction;
KW Transmembrane; Transmembrane helix; Transport; Vision.
FT CHAIN 1 1503 Multidrug resistance-associated protein
FT 6.
FT /FTId=PRO_0000093366.
FT TOPO_DOM 1 31 Extracellular (By similarity).
FT TRANSMEM 32 52 Helical; Name=1; (By similarity).
FT TOPO_DOM 53 72 Cytoplasmic (By similarity).
FT TRANSMEM 73 93 Helical; Name=2; (By similarity).
FT TOPO_DOM 94 98 Extracellular (By similarity).
FT TRANSMEM 99 119 Helical; Name=3; (By similarity).
FT TOPO_DOM 120 131 Cytoplasmic (By similarity).
FT TRANSMEM 132 149 Helical; Name=4; (By similarity).
FT TOPO_DOM 150 167 Extracellular (By similarity).
FT TRANSMEM 168 188 Helical; Name=5; (By similarity).
FT TOPO_DOM 189 302 Cytoplasmic (By similarity).
FT TRANSMEM 303 323 Helical; Name=6; (By similarity).
FT TOPO_DOM 324 349 Extracellular (By similarity).
FT TRANSMEM 350 370 Helical; Name=7; (By similarity).
FT TOPO_DOM 371 426 Cytoplasmic (By similarity).
FT TRANSMEM 427 447 Helical; Name=8; (By similarity).
FT TOPO_DOM 448 450 Extracellular (By similarity).
FT TRANSMEM 451 471 Helical; Name=9; (By similarity).
FT TOPO_DOM 472 533 Cytoplasmic (By similarity).
FT TRANSMEM 534 554 Helical; Name=10; (By similarity).
FT TOPO_DOM 555 575 Extracellular (By similarity).
FT TRANSMEM 576 596 Helical; Name=11; (By similarity).
FT TOPO_DOM 597 939 Cytoplasmic (By similarity).
FT TRANSMEM 940 960 Helical; Name=12; (By similarity).
FT TOPO_DOM 961 997 Extracellular (By similarity).
FT TRANSMEM 998 1018 Helical; Name=13; (By similarity).
FT TOPO_DOM 1019 1061 Cytoplasmic (By similarity).
FT TRANSMEM 1062 1082 Helical; Name=14; (By similarity).
FT TOPO_DOM 1083 1083 Extracellular (By similarity).
FT TRANSMEM 1084 1104 Helical; Name=15; (By similarity).
FT TOPO_DOM 1105 1175 Cytoplasmic (By similarity).
FT TRANSMEM 1176 1196 Helical; Name=16; (By similarity).
FT TOPO_DOM 1197 1198 Extracellular (By similarity).
FT TRANSMEM 1199 1219 Helical; Name=17; (By similarity).
FT TOPO_DOM 1220 1503 Cytoplasmic (By similarity).
FT DOMAIN 311 593 ABC transmembrane type-1 1.
FT DOMAIN 629 853 ABC transporter 1.
FT DOMAIN 947 1228 ABC transmembrane type-1 2.
FT DOMAIN 1265 1499 ABC transporter 2.
FT NP_BIND 663 670 ATP 1 (Potential).
FT NP_BIND 1299 1306 ATP 2 (Potential).
FT CARBOHYD 15 15 N-linked (GlcNAc...) (Probable).
FT VAR_SEQ 75 99 LGFALIVLCTSSVAVALWKIQQGTP -> AAIPGSLEPGNV
FT RGRQGTGWNLVKS (in isoform 2).
FT /FTId=VSP_047315.
FT VAR_SEQ 100 1503 Missing (in isoform 2).
FT /FTId=VSP_047316.
FT VARIANT 60 62 Missing (in PXE; autosomal recessive).
FT /FTId=VAR_013363.
FT VARIANT 61 61 G -> D.
FT /FTId=VAR_013364.
FT VARIANT 64 64 R -> W.
FT /FTId=VAR_013365.
FT VARIANT 74 74 Missing (in PXE).
FT /FTId=VAR_067840.
FT VARIANT 78 78 A -> T.
FT /FTId=VAR_067841.
FT VARIANT 125 125 E -> K (in dbSNP:rs3853814).
FT /FTId=VAR_067842.
FT VARIANT 129 129 G -> E (in PXE; autosomal recessive).
FT /FTId=VAR_067843.
FT VARIANT 158 158 A -> V.
FT /FTId=VAR_067844.
FT VARIANT 207 207 G -> R.
FT /FTId=VAR_013366.
FT VARIANT 265 265 R -> G (in dbSNP:rs78629019).
FT /FTId=VAR_013367.
FT VARIANT 281 281 K -> E (in dbSNP:rs4780606).
FT /FTId=VAR_013368.
FT VARIANT 317 317 S -> R (in PXE; autosomal recessive;
FT dbSNP:rs78678589).
FT /FTId=VAR_067845.
FT VARIANT 319 319 I -> V (in dbSNP:rs72657699).
FT /FTId=VAR_013369.
FT VARIANT 355 355 L -> R (in GACI2 and PXE; autosomal
FT recessive; dbSNP:rs72653758).
FT /FTId=VAR_067846.
FT VARIANT 363 373 Missing (in PXE).
FT /FTId=VAR_067847.
FT VARIANT 364 364 T -> R (in PXE; autosomal recessive).
FT /FTId=VAR_013370.
FT VARIANT 370 370 N -> D (in PXE; autosomal recessive;
FT dbSNP:rs72653760).
FT /FTId=VAR_067848.
FT VARIANT 382 382 R -> W (in PXE; dbSNP:rs72653761).
FT /FTId=VAR_067849.
FT VARIANT 391 391 R -> G (in GACI2 and PXE; autosomal
FT recessive; dbSNP:rs72653762).
FT /FTId=VAR_067850.
FT VARIANT 392 392 K -> N (in PXE).
FT /FTId=VAR_067851.
FT VARIANT 398 398 S -> G (in PXE; autosomal recessive;
FT dbSNP:rs72653764).
FT /FTId=VAR_067852.
FT VARIANT 411 411 N -> K (in PXE; autosomal dominant;
FT dbSNP:rs9930886).
FT /FTId=VAR_013371.
FT VARIANT 417 417 V -> M.
FT /FTId=VAR_067853.
FT VARIANT 440 440 C -> G (in PXE; autosomal recessive;
FT dbSNP:rs72653766).
FT /FTId=VAR_067854.
FT VARIANT 455 455 A -> P (in PXE; autosomal dominant;
FT dbSNP:rs67996819).
FT /FTId=VAR_013372.
FT VARIANT 463 463 L -> H (in PXE; dbSNP:rs72653767).
FT /FTId=VAR_067855.
FT VARIANT 495 495 L -> H (in PXE; autosomal recessive;
FT dbSNP:rs72653769).
FT /FTId=VAR_067856.
FT VARIANT 497 497 N -> K (in dbSNP:rs72653770).
FT /FTId=VAR_013373.
FT VARIANT 514 514 V -> I (in dbSNP:rs59157279).
FT /FTId=VAR_067857.
FT VARIANT 518 518 R -> Q (in PXE; autosomal recessive;
FT dbSNP:rs72653772).
FT /FTId=VAR_013374.
FT VARIANT 535 535 S -> P (in PXE; dbSNP:rs72653773).
FT /FTId=VAR_067858.
FT VARIANT 551 551 F -> S (in PXE; autosomal recessive;
FT dbSNP:rs72653774).
FT /FTId=VAR_067859.
FT VARIANT 568 568 F -> S (in PXE; autosomal dominant;
FT dbSNP:rs66864704).
FT /FTId=VAR_013375.
FT VARIANT 590 590 S -> F (in GACI2).
FT /FTId=VAR_067860.
FT VARIANT 594 594 A -> V (in PXE; autosomal recessive;
FT dbSNP:rs72653776).
FT /FTId=VAR_067861.
FT VARIANT 600 600 R -> C (in PXE; autosomal recessive;
FT dbSNP:rs72653777).
FT /FTId=VAR_067862.
FT VARIANT 614 614 V -> A (in dbSNP:rs12931472).
FT /FTId=VAR_011490.
FT VARIANT 632 632 H -> Q (in dbSNP:rs8058694).
FT /FTId=VAR_013376.
FT VARIANT 663 663 G -> C (in PXE; dbSNP:rs72653780).
FT /FTId=VAR_067863.
FT VARIANT 665 665 V -> A (in dbSNP:rs4341770).
FT /FTId=VAR_055477.
FT VARIANT 673 673 L -> P (in PXE; autosomal dominant;
FT dbSNP:rs67470842).
FT /FTId=VAR_013377.
FT VARIANT 677 677 L -> P (in PXE; autosomal recessive;
FT dbSNP:rs72653782).
FT /FTId=VAR_067864.
FT VARIANT 698 698 Q -> P (in PXE; dbSNP:rs72653783).
FT /FTId=VAR_067865.
FT VARIANT 699 699 E -> D (in PXE; dbSNP:rs72653784).
FT /FTId=VAR_067866.
FT VARIANT 724 724 R -> K (in dbSNP:rs58073789).
FT /FTId=VAR_067867.
FT VARIANT 724 724 R -> L.
FT /FTId=VAR_067868.
FT VARIANT 726 726 L -> P (in PXE; dbSNP:rs72653785).
FT /FTId=VAR_067869.
FT VARIANT 742 742 I -> V (in dbSNP:rs59593133).
FT /FTId=VAR_067870.
FT VARIANT 751 751 M -> K (in PXE; dbSNP:rs72653786).
FT /FTId=VAR_067871.
FT VARIANT 755 755 G -> R (in PXE; dbSNP:rs72653787).
FT /FTId=VAR_067872.
FT VARIANT 760 760 R -> W (in PXE; autosomal recessive;
FT dbSNP:rs72653788).
FT /FTId=VAR_067873.
FT VARIANT 765 765 R -> Q (in PXE; autosomal dominant and
FT autosomal recessive; dbSNP:rs67561842).
FT /FTId=VAR_013378.
FT VARIANT 766 766 A -> D (in PXE; autosomal recessive;
FT dbSNP:rs72653789).
FT /FTId=VAR_067874.
FT VARIANT 777 777 D -> N (in PXE; dbSNP:rs72653790).
FT /FTId=VAR_067875.
FT VARIANT 807 807 R -> Q (in PXE; autosomal recessive;
FT dbSNP:rs72653794).
FT /FTId=VAR_067876.
FT VARIANT 807 807 R -> W (in PXE; autosomal recessive;
FT dbSNP:rs72653793).
FT /FTId=VAR_067877.
FT VARIANT 810 810 V -> M (in PXE; autosomal recessive;
FT dbSNP:rs72653795).
FT /FTId=VAR_067878.
FT VARIANT 811 811 T -> M (in PXE; dbSNP:rs72653796).
FT /FTId=VAR_067879.
FT VARIANT 820 820 A -> P (in PXE; autosomal recessive;
FT dbSNP:rs72653797).
FT /FTId=VAR_067880.
FT VARIANT 848 848 M -> V (in dbSNP:rs6416668).
FT /FTId=VAR_059108.
FT VARIANT 881 881 R -> S (in PXE; dbSNP:rs72653800).
FT /FTId=VAR_067881.
FT VARIANT 944 944 T -> I (in PXE; dbSNP:rs72653801).
FT /FTId=VAR_067882.
FT VARIANT 946 946 L -> I (in dbSNP:rs61340537).
FT /FTId=VAR_067883.
FT VARIANT 950 950 A -> T (in PXE; dbSNP:rs72657689).
FT /FTId=VAR_067884.
FT VARIANT 953 953 L -> H (in dbSNP:rs72657700).
FT /FTId=VAR_013379.
FT VARIANT 992 992 G -> R (in PXE; dbSNP:rs72657692).
FT /FTId=VAR_067885.
FT VARIANT 1036 1036 Missing (in GACI2 and PXE; autosomal
FT recessive).
FT /FTId=VAR_067886.
FT VARIANT 1048 1048 Missing (in PXE; autosomal recessive).
FT /FTId=VAR_067887.
FT VARIANT 1056 1056 D -> E (in PXE; dbSNP:rs72657694).
FT /FTId=VAR_067888.
FT VARIANT 1064 1064 R -> W (in dbSNP:rs41278174).
FT /FTId=VAR_067889.
FT VARIANT 1097 1097 L -> I (in dbSNP:rs60707953).
FT /FTId=VAR_060988.
FT VARIANT 1114 1114 R -> C (in GACI2 and PXE; autosomal
FT recessive; dbSNP:rs63749794).
FT /FTId=VAR_067890.
FT VARIANT 1114 1114 R -> P (in PXE; autosomal recessive).
FT /FTId=VAR_011491.
FT VARIANT 1121 1121 S -> L (in PXE).
FT /FTId=VAR_067891.
FT VARIANT 1121 1121 S -> W (in PXE; autosomal dominant).
FT /FTId=VAR_013380.
FT VARIANT 1130 1130 T -> M (in PXE; autosomal recessive;
FT dbSNP:rs63750459).
FT /FTId=VAR_067892.
FT VARIANT 1133 1133 G -> A (in PXE; dbSNP:rs63750473).
FT /FTId=VAR_067893.
FT VARIANT 1138 1138 R -> P (in PXE; autosomal dominant).
FT /FTId=VAR_013381.
FT VARIANT 1138 1138 R -> Q (in PXE; autosomal recessive;
FT dbSNP:rs60791294).
FT /FTId=VAR_011492.
FT VARIANT 1138 1138 R -> W (in PXE; autosomal recessive;
FT dbSNP:rs28939701).
FT /FTId=VAR_011493.
FT VARIANT 1139 1139 A -> T (in PXE; dbSNP:rs63750146).
FT /FTId=VAR_067894.
FT VARIANT 1164 1164 R -> Q (in PXE; autosomal recessive;
FT dbSNP:rs63750457).
FT /FTId=VAR_067895.
FT VARIANT 1203 1203 G -> D (in PXE; autosomal dominant;
FT dbSNP:rs63750607).
FT /FTId=VAR_013382.
FT VARIANT 1221 1221 R -> C (in PXE; autosomal recessive;
FT dbSNP:rs63751215).
FT /FTId=VAR_067896.
FT VARIANT 1221 1221 R -> H (in GACI2; dbSNP:rs63751001).
FT /FTId=VAR_067897.
FT VARIANT 1226 1226 L -> I (in PXE; dbSNP:rs63750125).
FT /FTId=VAR_067898.
FT VARIANT 1235 1235 R -> W (in PXE; autosomal recessive;
FT dbSNP:rs63750402).
FT /FTId=VAR_067899.
FT VARIANT 1238 1238 D -> H (in PXE; pseudodominant;
FT dbSNP:rs63749796).
FT /FTId=VAR_067900.
FT VARIANT 1241 1241 W -> C (in dbSNP:rs72657701).
FT /FTId=VAR_013383.
FT VARIANT 1268 1268 R -> Q (associated with lower plasma
FT triglycerides and higher plasma HDL
FT cholesterol; dbSNP:rs2238472).
FT /FTId=VAR_011494.
FT VARIANT 1298 1298 V -> F (in PXE; autosomal dominant;
FT abolishes LTC4 and NEM-GS transport).
FT /FTId=VAR_013384.
FT VARIANT 1301 1301 T -> I (in PXE; autosomal dominant;
FT dbSNP:rs63750494).
FT /FTId=VAR_013385.
FT VARIANT 1302 1302 G -> R (in PXE; autosomal dominant and
FT autosomal recessive; abolishes LTC4 and
FT NEM-GS transport; dbSNP:rs63749856).
FT /FTId=VAR_013386.
FT VARIANT 1303 1303 A -> P (in PXE; autosomal dominant and
FT autosomal recessive).
FT /FTId=VAR_013387.
FT VARIANT 1314 1314 R -> Q (in PXE; autosomal dominant and
FT autosomal recessive).
FT /FTId=VAR_013388.
FT VARIANT 1314 1314 R -> W (in GACI2 and PXE; autosomal
FT recessive; dbSNP:rs63750759).
FT /FTId=VAR_011495.
FT VARIANT 1321 1321 G -> S (in PXE; autosomal dominant;
FT abolishes LTC4 and NEM-GS transport;
FT dbSNP:rs63749823).
FT /FTId=VAR_013389.
FT VARIANT 1335 1335 L -> P (in PXE; autosomal recessive).
FT /FTId=VAR_067901.
FT VARIANT 1335 1335 L -> Q (in PXE; dbSNP:rs63750414).
FT /FTId=VAR_067902.
FT VARIANT 1339 1339 R -> C (in PXE; autosomal recessive;
FT dbSNP:rs28939702).
FT /FTId=VAR_013390.
FT VARIANT 1339 1339 R -> H (in PXE; autosomal recessive;
FT dbSNP:rs63750622).
FT /FTId=VAR_067904.
FT VARIANT 1339 1339 R -> L (in PXE; autosomal recessive).
FT /FTId=VAR_067903.
FT VARIANT 1346 1346 P -> S (in PXE; autosomal recessive;
FT dbSNP:rs63751112).
FT /FTId=VAR_067905.
FT VARIANT 1347 1347 Q -> H (in PXE; autosomal dominant;
FT dbSNP:rs67720869).
FT /FTId=VAR_013391.
FT VARIANT 1354 1354 G -> R (in PXE; autosomal recessive;
FT dbSNP:rs63750018).
FT /FTId=VAR_013392.
FT VARIANT 1357 1357 R -> W (in PXE; autosomal recessive;
FT dbSNP:rs63750428).
FT /FTId=VAR_067906.
FT VARIANT 1361 1361 D -> N (in PXE; autosomal dominant;
FT dbSNP:rs58695352).
FT /FTId=VAR_013393.
FT VARIANT 1400 1400 E -> K (in PXE; autosomal recessive;
FT dbSNP:rs63751241).
FT /FTId=VAR_067907.
FT VARIANT 1406 1406 Q -> K (in PXE; autosomal recessive).
FT /FTId=VAR_067908.
FT VARIANT 1424 1424 I -> T (in PXE; autosomal dominant;
FT dbSNP:rs63750295).
FT /FTId=VAR_013394.
FT VARIANT 1459 1459 R -> C (in PXE; putative autosomal
FT dominant; dbSNP:rs72547524).
FT /FTId=VAR_067909.
FT CONFLICT 377 377 L -> P (in Ref. 1; AAD51293).
FT CONFLICT 1274 1274 Y -> C (in Ref. 1; AAD51293).
FT CONFLICT 1455 1455 L -> P (in Ref. 1; AAD51293).
SQ SEQUENCE 1503 AA; 164906 MW; 2107BE13B1547B39 CRC64;
MAAPAEPCAG QGVWNQTEPE PAATSLLSLC FLRTAGVWVP PMYLWVLGPI YLLFIHHHGR
GYLRMSPLFK AKMVLGFALI VLCTSSVAVA LWKIQQGTPE APEFLIHPTV WLTTMSFAVF
LIHTERKKGV QSSGVLFGYW LLCFVLPATN AAQQASGAGF QSDPVRHLST YLCLSLVVAQ
FVLSCLADQP PFFPEDPQQS NPCPETGAAF PSKATFWWVS GLVWRGYRRP LRPKDLWSLG
RENSSEELVS RLEKEWMRNR SAARRHNKAI AFKRKGGSGM KAPETEPFLR QEGSQWRPLL
KAIWQVFHST FLLGTLSLII SDVFRFTVPK LLSLFLEFIG DPKPPAWKGY LLAVLMFLSA
CLQTLFEQQN MYRLKVLQMR LRSAITGLVY RKVLALSSGS RKASAVGDVV NLVSVDVQRL
TESVLYLNGL WLPLVWIVVC FVYLWQLLGP SALTAIAVFL SLLPLNFFIS KKRNHHQEEQ
MRQKDSRARL TSSILRNSKT IKFHGWEGAF LDRVLGIRGQ ELGALRTSGL LFSVSLVSFQ
VSTFLVALVV FAVHTLVAEN AMNAEKAFVT LTVLNILNKA QAFLPFSIHS LVQARVSFDR
LVTFLCLEEV DPGVVDSSSS GSAAGKDCIT IHSATFAWSQ ESPPCLHRIN LTVPQGCLLA
VVGPVGAGKS SLLSALLGEL SKVEGFVSIE GAVAYVPQEA WVQNTSVVEN VCFGQELDPP
WLERVLEACA LQPDVDSFPE GIHTSIGEQG MNLSGGQKQR LSLARAVYRK AAVYLLDDPL
AALDAHVGQH VFNQVIGPGG LLQGTTRILV THALHILPQA DWIIVLANGA IAEMGSYQEL
LQRKGALMCL LDQARQPGDR GEGETEPGTS TKDPRGTSAG RRPELRRERS IKSVPEKDRT
TSEAQTEVPL DDPDRAGWPA GKDSIQYGRV KATVHLAYLR AVGTPLCLYA LFLFLCQQVA
SFCRGYWLSL WADDPAVGGQ QTQAALRGGI FGLLGCLQAI GLFASMAAVL LGGARASRLL
FQRLLWDVVR SPISFFERTP IGHLLNRFSK ETDTVDVDIP DKLRSLLMYA FGLLEVSLVV
AVATPLATVA ILPLFLLYAG FQSLYVVSSC QLRRLESASY SSVCSHMAET FQGSTVVRAF
RTQAPFVAQN NARVDESQRI SFPRLVADRW LAANVELLGN GLVFAAATCA VLSKAHLSAG
LVGFSVSAAL QVTQTLQWVV RNWTDLENSI VSVERMQDYA WTPKEAPWRL PTCAAQPPWP
QGGQIEFRDF GLRYRPELPL AVQGVSFKIH AGEKVGIVGR TGAGKSSLAS GLLRLQEAAE
GGIWIDGVPI AHVGLHTLRS RISIIPQDPI LFPGSLRMNL DLLQEHSDEA IWAALETVQL
KALVASLPGQ LQYKCADRGE DLSVGQKQLL CLARALLRKT QILILDEATA AVDPGTELQM
QAMLGSWFAQ CTVLLIAHRL RSVMDCARVL VMDKGQVAES GSPAQLLAQK GLFYRLAQES
GLV
//

MIM 264800
*RECORD*
*FIELD* NO
264800
*FIELD* TI
#264800 PSEUDOXANTHOMA ELASTICUM; PXE
;;GRONBLAD-STRANDBERG SYNDROME
PSEUDOXANTHOMA ELASTICUM, MODIFIER OF SEVERITY OF, INCLUDED;;
read morePXE, MODIFIER OF SEVERITY OF, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because in the overwhelming
majority of cases pseudoxanthoma elasticum (PXE), homozygosity or
compound heterozygosity is found for mutations in the ABCC6 gene
(603234), i.e., PXE is an autosomal recessive disorder. However,
carriers of heterozygous mutation in ABCC6 manifest partial
manifestations of the disorder (177850). It is thought that instances in
which the disease occurs in 2 generations can be attributed to
pseudodominance (Bergen, 2006; Ringpfeil et al., 2006; Chassaing et al.,
2005; Miksch et al., 2005).

Polymorphisms in the genes encoding xylosyltransferase, XYLT1 (608124)
and XYLT2 (608125) have been reported to modify the severity of PXE.

DESCRIPTION

Pseudoxanthoma elasticum is an inherited multisystem disorder that is
associated with accumulation of mineralized and fragmented elastic
fibers in the skin, vascular walls, and Burch membrane in the eye.
Clinically, patients exhibit characteristic lesions of the posterior
segment of the eye including peau d'orange, angioid streaks, and
choroidal neovascularizations, of the skin including soft, ivory colored
papules in a reticular pattern that predominantly affect the neck and
large flexor surfaces, and of the cardiovascular system with peripheral
and coronary arterial occlusive disease as well as gastrointestinal
bleedings (summary by Finger et al., 2009).

Generalized arterial calcification of infancy-2 (GACI2; 614473) is an
allelic disorder, also caused by homozygous or compound heterozygous
mutation in the ABCC6 gene; it has been suggested that GACI and PXE
represent 2 ends of a clinical spectrum of ectopic calcification and
other organ pathologies rather than 2 distinct disorders (Nitschke et
al., 2012).

CLINICAL FEATURES

Rigal (1881) is credited with the first description of the skin changes
in PXE, and Balzer (1884) provided the first autopsy report. The term
'pseudoxanthoma elasticum' was established by Darier (1896), who
histologically demonstrated an abnormality in elastin. Gronblad (1929),
a Swedish ophthalmologist, and Strandberg (1929), a Swedish
dermatologist, established the relationship of PXE and angioid streaks
in the retina (McKusick, 1972).

Goodman et al. (1963) provided a detailed clinical and histopathologic
study of 12 patients with PXE. They noted that the condition had been
referred to by several different names since it was first described in
1881. Eight of 12 patients noted skin changes since early childhood,
usually on the neck and in the axilla. Changes included accentuated fine
lines, redundant skin folds, and lesions consisting of yellowish papules
or plaques. Skin changes were also present in the inguinal folds,
antecubital and popliteal spaces, and oral, rectal, and vaginal mucosa.
Ocular involvement included pigmentary changes, angioid streaks,
chorioretinal scarring, and some loss of vision. Five of the 12 patients
had gastrointestinal bleeding. Arteriography demonstrated narrowing or
occlusion of peripheral arteries with marked collateral circulation,
particularly in the upper extremities. Histopathologic studies of skin,
heart, and vessels showed calcium deposition in elastic fibers.

Cartwright et al. (1969) described metachromatic fibroblasts in PXE. By
electron microscopy, Ross et al. (1978) demonstrated that the changes in
elastic fibers in individuals with PXE involve elastin whereas the
microfibrillar component is unchanged. The elastin had a granular
appearance, an increased affinity for cations, and often demonstrated
increased density presumed to represent foci of calcification. Similar
changes were found in clinically unaffected relatives. In 3 families the
inheritance was consistent with the autosomal recessive mode and 1 of
the presumed heterozygotes showed electron microscopic changes. In 1
kindred (reported also by Altman et al., 1974), the inheritance was
apparently more complex than either autosomal dominant or recessive.

McKusick (1972) presented autopsy findings of endocardial thickening in
PXE with degeneration and calcification of elastic fibers and with
collagenosis similar to that seen in the skin. Reviewing some of the
same autopsy cases, Mendelsohn et al. (1978) emphasized the severe
atherosclerosis present in all, resembling that encountered routinely.
Fragmentation and degeneration of the elastic laminae of muscular
arteries was followed by vascular calcification which could not be
distinguished morphologically from Monckeberg arteriosclerosis. There
was striking intimal fibroelastotic thickening, particularly in
intrarenal arteries. Like McKusick (1972), Mendelsohn et al. (1978)
emphasized the striking endocardial changes, e.g., in the right atrium.

Elejalde et al. (1984) described a 30-year-old woman with PXE who was
followed during pregnancy with several fetal ultrasonographic
examinations; these showed normal development up to week 26, followed by
a marked deceleration of fetal growth. The ultrasonographic appearance
of the placenta was abnormal at all times. The baby, born after 36
weeks, was small for gestational age due probably to placental
abnormality: the cotyledons were small and more numerous than normal;
one-third of the placenta was hypoplastic or atrophic with focal
calcification; and striking abnormalities of the elastic lamellae were
found in the maternal vessels. Fournier (1984) reported a well-studied
patient with PXE from an isolate in the Swiss Valais canton and by
genealogic research demonstrated relatedness of several affected
families in the region. Livedo reticularis and microaneurysms of
intrarenal arteries were observed.

Challenor et al. (1988) described a 27-year-old man with PXE who
presented with pulmonary edema resulting from restrictive left
ventricular cardiomyopathy caused by calcified endocardial bands. The
bands were resected as far as possible and the involved mitral valve was
replaced by a heterograft. A year later calcification of the heterograft
forced its replacement by a St. Jude prosthesis. Relief of symptoms was
satisfactory.

Fukuda et al. (1992) described a 54-year-old woman with PXE who over a
year of observation developed tight mitral stenosis without
regurgitation after having moderate mitral regurgitation due to mitral
valve prolapse. Endocardial changes of characteristic type were
demonstrated by myocardial biopsy of the right ventricle. It was thought
that the echocardiographic findings differed from those in classic
rheumatic mitral stenosis. Lebwohl et al. (1993) described 4 patients
who presented with premature cardiovascular disease and had angioid
streaks but no clinically discernible skin changes of PXE.
Characteristic fragmentation and clumping of elastic fibers in the
middle and deep dermis with calcification of elastic tissue was
demonstrated in all 4 patients. Two of the patients were sisters, aged
27 and 39 years. The younger sister had 4-vessel coronary artery bypass
surgery. Multiple arterial biopsies showed calcification of the internal
elastic laminae. A 41-year-old brother was subsequently found to have
angioid streaks. The father, who died at the age of 69, had a history of
retinal hemorrhage.

In a nationwide study in South Africa and Zimbabwe, Viljoen et al.
(1987) identified 64 patients with PXE. In the opinion of these workers,
39 of the patients comprised a distinct clinical subgroup of PXE
characterized by autosomal recessive inheritance and severe visual
impairment out of proportion to the degree of involvement of the skin.
In 40% of individuals, severe hypertension and occasionally angina or
claudication were also present. The 39 affected individuals were found
exclusively among persons of Afrikaner descent. Viljoen et al. (1987)
noted that the 'Afrikaner' form and other forms of PXE are
indistinguishable on histology, electron microscopy, or biochemistry,
and that clinical differences may not be significant. For example,
McKusick (1960) had pointed out the occurrence of inconspicuous skin
changes despite severe ocular changes. De Paepe et al. (1991) reported
on the clinical and genetic characteristics of 26 Belgian and 32
Afrikaner families with PXE. The phenotype in both groups was
characterized by severe ophthalmologic manifestations with milder,
variable cutaneous and vascular symptoms. The authors reiterated the
suggestion that the PXE phenotype in these Belgian and Afrikaner
families is distinct from previously described PXE phenotypes.

There have been isolated case reports of arterial and skin calcification
in mammograms of patients with pseudoxanthoma elasticum, and unpublished
anecdotes of many women with PXE undergoing breast biopsy for evaluation
of microcalcifications. Bercovitch et al. (2003) systematically
evaluated mammography and breast pathology in 51 women with confirmed
PXE and compared them with those of a control sample of 109 women
without PXE. Breast density, skin thickening, skin microcalcifications,
vascular calcification, breast microcalcifications and
macrocalcifications, and masses were evaluated specifically. The PXE and
control groups were similar in age and indications for mammography.
Bercovitch et al. (2003) found a statistically significant increase in
skin thickening, vascular calcification, and breast microcalcifications
in the PXE group (P less than 0.001 each). Breast density, masses,
macrocalcifications, and skin calcification did not differ statistically
in the 2 groups, but no control patient had axillary calcification, or
both vascular calcification and microcalcifications (p less than 0.001).
About 1 in 7 of the patients with PXE demonstrated at least 3 of the
following: microcalcifications, skin calcifications, vascular
calcification, and skin thickening; however, none of the control group
did. Histopathologic findings of breast tissue showed calcification of
dermal elastic fibers, subcutaneous arteries, and elastic fibers of the
deep fascia and interlobular septae of the fat adjacent to breast
parenchyma. Bercovitch et al. (2003) concluded that breast
microcalcification and arterial calcification are not rare in the normal
population and are not of diagnostic value. However, the presence of
both of these findings, especially with skin thickening or axillary skin
calcification, should suggest a diagnosis of PXE. The majority of breast
calcifications in PXE are benign.

- Intrafamilial Phenotypic Variability

Le Boulanger et al. (2010) studied a nonconsanguineous French family in
which an older brother developed uncomplicated PXE in adolescence,
whereas a younger brother died of a condition 'strikingly reminiscent'
of generalized arterial calcification of infancy (GACI2; 614473) at 15
months of age. The younger brother had a myocardial infarction
complicated by heart failure at 6 months of age, and skin biopsy at 1
year of age for evaluation of a possible connective tissue disorder
showed elastic fiber dystrophy, with clumped and fragmented fibers in
the mid dermis, as well as calcifications on the elastic fibers and
sporadically in vessel walls of the subcutis. At 15 months of age, he
had a second, fatal MI, and autopsy showed fibrosis of the coronary
arteries with calcifications involving the intima, internal elastic
lamina, and media. At 28 years of age, the older brother presented for
evaluation of yellowish papules on his neck; he had no cardiovascular
symptoms and cardiac examination and echocardiography were normal. Skin
samples from the brother with PXE showed heavy staining of mineralized
mid-dermal elastic fibers, with active MGP (154870) and fetuin-A
(138680) antibodies, and fetuin-A also showed striking staining of the
subepidermal area. All arteries in autopsy samples from the brother with
GACI showed the same immunohistochemical profile, as well as
calcifications.

DIAGNOSIS

Lebwohl et al. (1987) biopsied scars as well as flexural skin from 10
patients with angioid streaks but without cutaneous findings indicative
of PXE. In 6 of the 10 patients, scar biopsies showed fragmentation and
clumping of elastic tissue in the deep dermis. Three patients also had
histologic changes of PXE in biopsy specimens of flexural skin that
appeared normal. The authors concluded that scar biopsies may be useful
in diagnosis when PXE is suspected despite the absence of typical skin
lesions.

In a report of a consensus conference on PXE, Lebwohl et al. (1994)
stated that histologic evidence of calcified elastic fibers is essential
for diagnosis. The group proposed a provisional classification system of
PXE patients who may lack one or more of the 3 major criteria: skin,
eye, or cardiovascular involvement. However, the group also noted that
in time, all patients with PXE tend to merge into a single classic
phenotype with all 3 features, and that separation into subtypes based
on phenotype is difficult.

Struk et al. (1997) noted that the 'gold standard' for diagnosis of PXE
is positive von Kossa staining showing calcification and fracture of
elastic fibers in biopsy material from affected skin.

Plomp et al. (2010) reviewed the major clinical signs of PXE and
proposed an updated classification system for the disorder, including
revised diagnostic criteria. Diagnostic criteria included skin findings
confirmed by skin biopsy, ocular findings corroborated by funduscopy,
and mutation analysis of the ABCC6 gene. Additional minor criteria
included the findings of 'comets' in the retina or 'pigmented wing'
signs in the retina. Patients can be classified as having a definite,
probable, or possible diagnosis based on the number of signs present.

- Differential Diagnosis

The occurrence of angioid streaks in homozygous thalassemia and in
sickle cell anemia has been attributed to the deposition of iron in
Bruch membrane behind the retina. Severe ophthalmologic complications
like those of PXE may occur in some cases (Aessopos et al., 1989).
Angioid streaks in hemochromatosis are presumably also a reflection of
iron deposits. The occurrence of angioid streaks with Paget disease of
bone (167250) and with tumoral calcinosis with hyperphosphatemia
(211900) may be related to the deposition of calcium in a relatively
normal Bruch membrane. Angioid streaks are said to occur with lead
poisoning (Clarkson and Altman, 1982). Aessopos et al. (1992) suggested
that beta-thalassemia must be considered in the differential diagnosis
of PXE because of the occurrence of PXE-like skin lesions as well as
angioid streaks. In 62 patients with homozygous beta-thalassemia major
and 38 with beta-thalassemia intermedia, they found diagnostic skin
lesions in 16 patients. Angioid streaks were found in 20 of the 100
patients, and both PXE skin lesions and angioid streaks were found in 10
of the patients; in all, 26 had either one or both of these
manifestations. A positive correlation was found between the presence of
one or both types of lesion and age of the patients; there were no
differences in regard to ferritin and hematocrit levels, number of
transfused units, chelation therapy, and splenic status between patients
with or without the findings of PXE. One might wonder about iron loading
as the mechanism of the PXE-like changes. Angioid streaks were described
in homozygous sickle cell disease by Nagpal et al. (1976), Hamilton et
al. (1981), and others. Aessopos et al. (2002) reviewed elastic tissue
abnormalities resembling PXE in beta-thalassemia and sickling syndromes.

Hamlin et al. (2003) reported the clinical and histopathologic
manifestations of 10 beta-thalassemia patients with PXE-like skin
lesions in combination with ocular and/or vascular symptoms and
calcified elastic fibers. No disease-causing variant was found in the
ABCC6 (603234) gene, indicating that this was a phenocopy of PXE. Hamlin
et al. (2003) discussed the hypothesis that as iron loading progresses
in beta-thalassemic patients, the capacity for the transport and storage
of iron may be exceeded, and a fraction of iron that is not bound to
transferrin or ferritin may promote the generation of free radicals,
which are in turn propagators of oxidation-related damage to various
organs and tissues, including elastin-rich tissues.

INHERITANCE

The assessment of inheritance in PXE has been complicated by clinical
heterogeneity and variable age of onset (Neldner, 1988).

Miksch et al. (2005) performed a mutation screen in ABCC6 using
haplotype analysis in conjunction with direct sequencing to achieve a
mutation detection rate of 97%. Their mutation analysis confirmed an
earlier haplotype-based analysis and conclusions regarding a
recessive-only mode of inheritance in PXE (Cai et al., 2000) through the
identification of 2 mutated alleles in all individuals with PXE who
appear in either consecutive or alternating generations of the same
family. Their study demonstrated that the full phenotypic expression of
the disorder requires 2 defective allelic copies of ABCC6 and that
pseudodominance is the mode of transmission in presumed autosomal
dominant families (i.e., the second parental disease allele 'marries
into' the family). The apparent frequency of this mechanism was
approximately 7.5% in their family cohort. Miksch et al. (2005) stated
that in their families no heterozygote for a large deletion showed any
apparent clinical sign of PXE according to category I diagnostic
criteria.

To determine the exact mode of inheritance of PXE, Ringpfeil et al.
(2006) identified 7 pedigrees with affected individuals in 2 different
generations and sequenced the entire coding region of ABCC6 in affected
persons and in presumed carriers with a limited phenotype, as well as
unaffected family members. Two allelic mutations were identified in each
individual with unambiguous diagnosis of PXE, as well as in those with
only minimal clinical signs suggestive of PXE but with positive skin
biopsy. Missense mutations were frequently detected in the latter cases.
Ringpfeil et al. (2006) concluded that PXE is inherited as an autosomal
recessive and that those instances in which the disease occurs in 2
generations can be attributed to pseudodominance. Bergen (2006)
maintained that this and other work such as that of Chassaing et al.
(2005) and Miksch et al. (2005) puts an end to the 'autosomal dominant
segregation myth' (see HISTORY).

PATHOGENESIS

Since the ABCC6 gene (603234) is expressed primarily, if not
exclusively, in the liver and kidneys, Ringpfeil et al. (2001) suggested
that PXE is a primary metabolic disorder with secondary involvement of
elastic fibers, a situation comparable to the secondary involvement of
connective tissue elements in homocystinuria (236200) and alkaptonuria
(203500).

ABCC6 is a member of the large ATP-dependent transmembrane transporter
family. Chassaing et al. (2005) commented that the association of PXE to
ABCC6 efflux transport alterations raised a number of pathophysiology
hypotheses, among them the idea that PXE is a systemic metabolic disease
resulting from lack or accumulation over time in the bloodstream of
molecules interacting with the synthesis, turnover, and/or maintenance
of extracellular matrix (ECM).

Findings in mouse models (see ANIMAL MODEL) have also indicated that PXE
is a systemic metabolic disease (Jiang et al., 2009).

MAPPING

In an abstract presented at the Fifth International Workshop on Human
Chromosome 16, on 3-4 March 1997 in Toronto, and in a subsequent full
publication, Struk et al. (1997) reported a genomewide screen on a
collection of 38 families with 2 or more sibs with PXE. They used
allele-sharing algorithms, followed by high-resolution mapping and
analysis by conventional linkage algorithms in recessive and dominant
families. Excess allele-sharing was found on the short arm of chromosome
16 and confirmed by maximum-likelihood linkage analysis, localizing the
disease gene in recessive families to a 3.0-cM region on 16p13.1 with a
maximum 2-point lod score of 19.0. In dominant families, linkage to the
same region with a maximum 2-point lod score of 3.6 was observed. Struk
et al. (1997) predicted that allelic heterogeneity with different
variants of a single disease gene residing on 16p13.1 accounts for both
recessive and dominant forms of PXE.

In a family from a genetically isolated population in the Netherlands
suffering from autosomal recessive PXE, van Soest et al. (1997) combined
homozygosity mapping and genome scanning to map the PXE1 locus to
16p13.1. Initially, homozygosity was found in 2 or 3 patients with up to
20 markers, among which was D16S292 located in 16p13.1. Refined and more
extensive family screening of the latter region showed close linkage
without recombination with the marker D16S764 (maximum lod = 6.27).
Despite clear autosomal recessive inheritance of the ocular symptoms in
this disorder, vascular symptoms appeared in 40 to 50% of the
heterozygotes.

Le Saux et al. (1999) performed linkage analysis on 21 families with PXE
using 10 polymorphic markers located on 16p13.1. They localized the gene
to an 8-cM region of 16p13.1 between markers D16S500 and D16S3041 with a
maximum lod score of 8.1 at a recombination fraction of 0.04 for marker
D16S3017. They found no evidence of locus heterogeneity. Haplotype
studies of 36 PXE families identified several recombinations that
further confined the PXE gene to a region of less than 1 cM between
markers D16S3060 and D16S79. The PXE locus was identified within a
single YAC clone and several overlapping BAC recombinants.

MOLECULAR GENETICS

In several families with PXE, Ringpfeil et al. (2000), Bergen et al.
(2000), and Le Saux et al. (2000) identified mutations in the ABCC6
gene. Of 4 families with autosomal recessive inheritance of PXE reported
by Ringpfeil et al. (2000), 1 was compound heterozygous for mutations in
the ABCC6 gene (see, e.g., R1141X, 603234.0001), 1 family was hemizygous
for the R1141X mutation, and 2 families were homozygous for mutations.
Of 4 so-called sporadic cases, 1 was compound heterozygous and 3
appeared heterozygous for mutations in the ABCC6 gene. Bergen et al.
(2000) identified mutations in the ABCC6 gene in 2 sporadic patients
with PXE (see, e.g., 603234.0009), 4 families with PXE that appeared to
be autosomal dominant (see, e.g., 603234.0008), and 1 family with
autosomal recessive PXE (603234.0007). Le Saux et al. (2000) identified
mutations in the ABCC6 gene in 5 families with autosomal recessive PXE
and in 1 sporadic case (see, e.g., 603234.0001 and 603234.0002). The
R1141X mutation (603234.0001) was found in families segregating
autosomal recessive PXE and in families with expressing heterozygotes.

Using multiplex ligation-dependent probe amplification (MLPA) to analyze
35 PXE patients with incomplete ABCC6 genotypes after exonic sequencing,
Costrop et al. (2010) identified 6 multiexon deletions and 4 single-exon
deletions and were thus able to characterized 25% of the unidentified
disease alleles. The findings illustrated the instability of the ABCC6
genomic region and stressed the importance of screening for deletions in
the molecular diagnosis of PXE.

In a 28-year-old French man with pseudoxanthoma elasticum who had a
younger brother who died of generalized arterial calcification of
infancy (GACI2; 614473) at age 15 months, Le Boulanger et al. (2010)
identified compound heterozygosity for missense mutations in the ABCC6
gene (603234.0025 and 603234.0026), which were also found in
heterozygosity in each of his unaffected parents, respectively. No
disease-causing mutations were found in the ENPP1 gene (173335), which
is known to cause GACI1 (208000). Although no DNA material was available
from the deceased younger brother, his disease was presumed to be
related to the familial ABCC6 mutations. Le Boulanger et al. (2010)
concluded that GACI may represent an atypical and severe end of the
vascular phenotypic spectrum of PXE.

- PXE-Associated Retinopathy

Choroidal neovascularization (CNV) in PXE-associated retinopathy is
believed to be mediated by the action of VEGF (192240). Zarbock et al.
(2009) evaluated the distribution of 10 SNPs in the promoter and coding
region of the VEGFA gene in DNA samples from 163 German patients
affected by PXE and in 163 healthy control subjects. Haplotype analysis
identified an 8-SNP haplotype CTGGCCCC that was associated with PXE.
Furthermore, 5 SNPs showed significant association with severe
retinopathy. The most significant single SNP association was -460C-T
(dbSNP rs833061, OR = 3.83, 95% CI 2.01-7.31, corrected p = 0.0003).
Logistic regression analysis identified the dbSNP rs833061 and 674C-T
variant (dbSNP rs1413711; OR = 3.21, 95% CI 1.70-6.02, corrected p =
0.004) as independent risk factors for development of severe
retinopathy. Zarbock et al. (2009) suggested an involvement of VEGF in
the pathogenesis of ocular PXE manifestations.

- Modifier Genes

Schon et al. (2006) reported that polymorphisms in the XYLT1 and XYLT2
genes (608124.0001 and 608125.0001, respectively) modify the severity of
PXE.

POPULATION GENETICS

Struk et al. (1997) estimated that the prevalence of PXE, both the
recessive and dominant forms, is 1 in 70,000 to 100,000.

In a cohort of 122 unrelated PXE patients from various countries, Le
Saux et al. (2001) identified a G1321S missense mutation in the ABCC6
gene (603234.0021). The G1321S mutation was detected in heterozygosity
in 1 of 74 United States alleles, for an allele frequency of 1.4%, but
was not found in the European population.

Hu et al. (2003) demonstrated a founder effect for the R1141X mutation
(603234.0001) in the Netherlands. They identified the mutation in 19
alleles in 16 Dutch patients with PXE, in heterozygous, homozygous, or
compound heterozygous form. Expression of the normal allele in
heterozygotes was predominant; no or very low expression was found in
homozygotes. The mutation induced instability of the aberrant mRNA. Hu
et al. (2003) suggested that the PXE phenotype of the R1141X mutation
most likely results from complete loss of function or functional
haploinsufficiency of ABCC6.

ANIMAL MODEL

Gorgels et al. (2005) generated Abcc6 -/- mice and showed by light and
electron microscopy that Abcc6 -/- mice spontaneously developed
calcification of elastic fibers in blood vessel walls and in Bruch
membrane in the eye. No clear abnormalities were seen in the dermal
extracellular matrix. Calcification of blood vessels was most prominent
in small arteries in the cortex of the kidney, but in old mice, it
occurred also in other organs and in the aorta and vena cava. Monoclonal
antibodies against mouse Abcc6 localized the protein to the basolateral
membranes of hepatocytes and the basal membrane in renal proximal
tubules, but failed to show the protein at the pathogenic sites. Abcc6
-/- mice developed a 25% reduction in plasma HDL cholesterol and an
increase in plasma creatinine levels, which may be due to impaired
kidney function. No changes in serum mineral balance were found. Gorgels
et al. (2005) concluded that the phenotype of the Abcc6 -/- mouse shares
calcification of elastic fibers with human PXE pathology, and supports
the hypothesis that PXE is a systemic disease.

Jiang et al. (2009) found that grafting of wildtype mouse muzzle skin
onto the back of Abcc6-knockout mice resulted in abnormal mineralization
of vibrissae consistent with PXE, whereas grafting of Abcc6-knockout
mouse muzzle skin onto wildtype mice did not. The data implied that PXE
does not result from localized defect based on resident cellular
abnormalities but from a change of metabolite(s) in serum. These
findings implicate circulatory factors as a critical component of the
mineralization process and supported the notion that PXE is a secondary
mineralization of connective tissues. In addition, the findings
suggested that the abnormal mineralization process could possibly be
countered or even reversed by changes in the homeostatic milieu.

HISTORY

- Autosomal Dominant Inheritance

Pope (1974) suggested that there are 2 dominant and 2 recessive forms of
PXE (see below).

Neldner (1988) concluded that 97% of his patients had autosomal
recessive inheritance. His conclusion did not allow for new mutation
dominant cases.

In a report of a consensus conference, Lebwohl et al. (1994) stated that
both autosomal dominant and autosomal recessive forms of PXE exist, and
that no clinical features can distinguish between the 2 disorders.

Struk et al. (1997) stated that an autosomal dominant pattern of
transmission of PXE occurs in approximately 10% of affected families.

Plomp et al. (2004) reviewed the literature on autosomal dominant PXE.
They studied in detail, both clinically and by DNA studies, a selection
of potentially autosomal dominant pedigrees from a patient population
comprising 59 probands and their relatives. Individuals were considered
to have definite PXE if they had 2 of the following 3 criteria:
characteristic ophthalmologic signs, characteristic dermatologic signs,
and positive skin biopsy. In the literature, Plomp et al. (2004) found
only 3 families with definite PXE in 2 successive generations and no
families with definite PXE in 3 or more generations. Their own data set
included 3 putative autosomal dominant families. Extensive DNA studies
revealed a mutation in only 1 ABCC6 allele in the patients of these 3
families. Only 1 of the families showed definite PXE in 2 generations.
Linkage studies revealed that pseudodominance was unlikely in this
family. In the other 2 families, autosomal dominant PXE could not be
confirmed after extensive clinical examinations and application of the
criteria, since definite PXE was not present in 2 or more generations.
Plomp et al. (2004) concluded that the inheritance pattern in PXE is
autosomal recessive in the overwhelming majority of families.

Hu et al. (2004) cited the investigation of Plomp et al. (2004) as
indicating that autosomal dominant inheritance of PXE can be expected in
approximately 2% of cases.

- Classification

Pope (1974) suggested that there are 2 dominant and 2 recessive forms of
PXE. The type I recessive form was characterized by moderate vascular
and retinal degeneration accompanied by cutaneous lesions. The type II
recessive form was characterized by generalized skin changes with no
blood vessel or ocular manifestations, and was considered rare, being
present in 3 of 121 probands. Individuals with the type I dominant form
had severe retinal and cardiovascular degeneration, accompanied by the
cutaneous features. Those with the type II dominant form had mild
cardiovascular and retinal changes together with hyperextensible joints,
blue sclerae, and a high arched palate.

On the basis of his own extensive experience and that reported in the
literature, Neldner (1988) provided a critique of the Pope 4-subtype
classification. Whereas only 47% of 121 patients studied by Pope in the
U.K. were thought to have the recessive form, the more general
experience is that the recessive form of PXE is by far the more
frequent.

- Other Inheritance

Berlyne et al. (1961) suggested that PXE may be inherited as a partial
X-linked recessive (i.e., that the gene may be on a part of the X
chromosome homologous with part of the Y chromosome). If such were the
case, patients in any one sibship would tend always to be of the same
sex. This mode of inheritance was not supported by later work.

*FIELD* SA
Coffman and Sommers (1959); Messis and Budzilovich (1970); Pope (1975);
Renie et al. (1984); Sandberg et al. (1981); Viljoen (1988)
*FIELD* RF
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17. Darier, J.: Pseudoxanthoma elasticum. Monatshefte Prakt. Derm. 23:
609-617, 1896.

18. De Paepe, A.; Viljoen, D.; Matton, M.; Beighton, P.; Lenaerts,
V.; Vossaert, K.; De Bie, S.; Voet, D.; De Laey, J.-J.; Kint, A.:
Pseudoxanthoma elasticum: similar autosomal recessive subtype in Belgian
and Afrikaner families. Am. J. Med. Genet. 38: 16-20, 1991.

19. Elejalde, B. R.; Mercedes de Elejalde, M.; Samter, T.; Burgess,
J.; Lombardi, J.; Gilbert, E. F.: Manifestations of pseudoxanthoma
elasticum during pregnancy: a case report and review of the literature. Am.
J. Med. Genet. 18: 755-762, 1984.

20. Finger, R. P.; Issa, P. C.; Ladewig, M. S.; Gotting, C.; Szliska,
C.; Scholl, H. P. N.; Holz, F. G.: Pseudoxanthoma elasticum: genetics,
clinical manifestations and therapeutic approaches. Surv. Ophthalmol. 54:
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21. Fournier, D.: Le pseudoxanthome elastique, un syndrome meconnu:
a propos d'une observation clinique et genetique. Schweiz. Rundsch.
Med. Prax. 73: 183-191, 1984.

22. Fukuda, K.; Uno, K.; Fujii, T.; Mukai, M.; Handa, S.: Mitral
stenosis in pseudoxanthoma elasticum. Chest 101: 1706-1707, 1992.

23. Goodman, R. M.; Smith, E. W.; Paton, D.; Bergman, R. A.; Siegel,
C. L.; Ottesen, O. E.; Shelley, W. M.; Pusch, A. L.; McKusick, V.
A.: Pseudoxanthoma elasticum: a clinical and histopathological study. Medicine 42:
297-334, 1963.

24. Gorgels, T. G. M. F.; Hu, X.; Scheffer, G. L.; van der Wal, A.
C.; Toonstra, J.; de Jong, P. T. V. M.; van Kuppevelt, T. H.; Levelt,
C. N.; de Wolf, A.; Loves, W. J. P.; Scheper, R. J.; Peek, R.; Bergen,
A. A. B.: Disruption of Abcc6 in the mouse: novel insight in the
pathogenesis of pseudoxanthoma elasticum. Hum. Molec. Genet. 14:
1763-1773, 2005.

25. Gronblad, E.: Angioid streaks--pseudoxanthoma elasticum. Acta
Ophthal. 7: 329 only, 1929.

26. Hamilton, A. M.; Pope, F. M.; Condon, P. I.; Slavin, G.; Sowter,
C.; Ford, S.; Hayes, R. J.; Serjeant, G. R.: Angioid streaks in Jamaican
patients with homozygous sickle cell disease. Brit. J. Ophthal. 65:
341-347, 1981.

27. Hamlin, N.; Beck, K.; Bacchelli, B.; Cianciulli, P.; Pasquali-Ronchetti,
I.; Le Saux, O.: Acquired pseudoxanthoma elasticum-like syndrome
in beta-thalassaemia patients. Brit. J. Haemat. 122: 852-854, 2003.

28. Hu, X.; Peek, R.; Plomp, A.; ten Brink, J.; Scheffer, G.; van
Soest, S.; Leys, A.; de Jong, P. T. V. M.; Bergen, A. A. B.: Analysis
of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma
elasticum. Invest. Ophthal. Vis. Sci. 44: 1824-1829, 2003.

29. Hu, X.; Plomp, A.; Gorgels, T.; Ten Brink, J.; Loves, W.; Mannens,
M.; De Jong, P. T. V. M.; Bergen, A. A. B.: Efficient molecular diagnostic
strategy for ABCC6 in pseudoxanthoma elasticum. Genet. Test. 8:
292-300, 2004.

30. Jiang, Q.; Endo, M.; Dibra, F.; Wang, K.; Uitto, J.: Pseudoxanthoma
elasticum is a metabolic disease. J. Invest. Derm. 129: 348-354,
2009.

31. Le Boulanger, G.; Labreze, C.; Croue, A.; Schurgers, L. J.; Chassaing,
N.; Wittkampf, T.; Rutsch, F.; Martin, L.: An unusual severe vascular
case of pseudoxanthoma elasticum presenting as generalized arterial
calcification of infancy. Am. J. Med. Genet. 152A: 118-123, 2010.

32. Lebwohl, M.; Halperin, J.; Phelps, R. G.: Occult pseudoxanthoma
elasticum in patients with premature cardiovascular disease. New
Eng. J. Med. 329: 1237-1239, 1993.

33. Lebwohl, M.; Neldner, K.; Pope, F. M.; De Paepe, A.; Christiano,
A. M.; Boyd, C. D.; Uitto, J.; McKusick, V. A.: Classification of
pseudoxanthoma elasticum: report of a consensus conference. J. Am.
Acad. Derm. 30: 103-107, 1994.

34. Lebwohl, M.; Phelps, R. G.; Yannuzzi, L.; Chang, S.; Schwartz,
I.; Fuchs, W.: Diagnosis of pseudoxanthoma elasticum by scar biopsy
in patients without characteristic skin lesions. New Eng. J. Med. 317:
347-350, 1987.

35. Le Saux, O.; Beck, K.; Sachsinger, C.; Silvestri, C.; Treiber,
C.; Goring, H. H. H.; Johnson, E. W.; De Paepe, A.; Pope, F. M.; Pasquali-Ronchetti,
I.; Bercovitch, L.; Terry, S.; Boyd, C. D.: A spectrum of ABCC6 mutations
is responsible for pseudoxanthoma elasticum. Am. J. Hum. Genet. 69:
749-764, 2001. Note: Erratum: Am. J. Hum. Genet. 69: 1413 only, 2001;
Erratum: Am. J. Hum. Genet. 71: 448 only, 2002.

36. Le Saux, O.; Urban, Z.; Goring, H. H. H.; Csiszar, K.; Pope, F.
M.; Richards, A.; Pasquali-Ronchetti, I.; Terry, S.; Bercovitch, L.;
Lebwohl, M. G.; Breuning, M.; van den Berg, P.; Kornet, L.; Doggett,
N.; Ott, J.; de Jong, P. T. V. M.; Bergen, A. A. B.; Boyd, C. D.:
Pseudoxanthoma elasticum maps to an 820-kb region of the p13.1 region
of chromosome 16. Genomics 62: 1-10, 1999. Note: Erratum: Genomics
63: 439 only, 2000.

37. Le Saux, O.; Urban, Z.; Tschuch, C.; Csiszar, K.; Bacchelli, B.;
Quaglino, D.; Pasquali-Ronchetti, I.; Pope, F. M.; Richards, A.; Terry,
S.; Bercovitch, L.; de Paepe, A.; Boyd, C. D.: Mutations in a gene
encoding an ABC transporter cause pseudoxanthoma elasticum. Nature
Genet. 25: 223-227, 2000.

38. McKusick, V. A.: Heritable Disorders of Connective Tissue.
St. Louis: C. V. Mosby (pub.) (4th ed.): 1972. Pp. 475-520.

39. McKusick, V. A.: Heritable Disorders of Connective Tissue.
St. Louis: C. V. Mosby (pub.) (2nd ed.): 1960. P. 221 only. Note:
Fig. 78.

40. Mendelsohn, G.; Bulkley, B. H.; Hutchins, G. M.: Cardiovascular
manifestations of pseudoxanthoma elasticum. Arch. Path. Lab. Med. 102:
298-302, 1978.

41. Messis, C. P.; Budzilovich, G. N.: Pseudoxanthoma elasticum:
report of an autopsied case with cerebral involvement. Neurology 20:
703-709, 1970.

42. Miksch, S.; Lumsden, A.; Guenther, U. P.; Foernzler, D.; Christen-Zach,
S.; Daugherty, C.; Ramesar, R. S.; Lebwohl, M.; Hohl, D.; Neldner,
K. H.; Lindpaintner, K.; Richards, R. I.; Struk, B.: Molecular genetics
of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6. Hum.
Mutat. 26: 235-248, 2005.

43. Nagpal, K. C.; Asdourian, G.; Goldbaum, M.; Apple, D.; Goldberg,
M. F.: Angioid streaks and sickle haemoglobinopathies. Brit. J.
Ophthal. 60: 31-34, 1976.

44. Neldner, K. H.: Pseudoxanthoma elasticum. Clin. Derm. 6: 83-92,
1988.

45. Nitschke, Y.; Baujat, G.; Botschen, U.; Wittkampf, T.; du Moulin,
M.; Stella, J.; Le Merrer, M.; Guest, G.; Lambot, K.; Tazarourte-Pinturier,
M.-F.; Chassaing, N.; Roche, O.; and 19 others: Generalized arterial
calcification of infancy and pseudoxanthoma elasticum can be caused
by mutations in either ENPP1 or ABCC6. Am. J. Hum. Genet. 90: 25-39,
2012.

46. Plomp, A. S.; Hu, X.; de Jong, P. T. V. M.; Bergen, A. A. B.:
Does autosomal dominant pseudoxanthoma elasticum exist? Am. J. Med.
Genet. 126A: 403-412, 2004.

47. Plomp, A. S.; Toonstra, J.; Bergen, A. A. B.; van Dijk, M. R.;
de Jong, P. T. V. M.: Proposal for updating the pseudoxanthoma elasticum
classification system and a review of the clinical findings. Am.
J. Med. Genet. 152A: 1049-1058, 2010.

48. Pope, F. M.: Historical evidence for the genetic heterogeneity
of pseudoxanthoma elasticum. Brit. J. Derm. 92: 493-509, 1975.

49. Pope, F. M.: Two types of autosomal recessive pseudoxanthoma
elasticum. Arch. Derm. 110: 209-212, 1974.

50. Renie, W. A.; Pyeritz, R. E.; Combs, J.; Fine, S. L.: Pseudoxanthoma
elasticum: high calcium intake in early life correlates with severity. Am.
J. Med. Genet. 19: 235-244, 1984.

51. Rigal, (NI): Observation pour servir a l'histoire de la cheloide
diffuse xanthelasmique. Ann. Derm. Syph. 21: 491-501, 1881.

52. Ringpfeil, F.; Lebwohl, M.G.; Christiano, A. M.; Uitto, J.: Pseudoxanthoma
elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding
cassette (ABC) transporter. Proc. Nat. Acad. Sci. 97: 6001-6006,
2000.

53. Ringpfeil, F.; McGuigan, K.; Fuchsel, L.; Kozic, H.; Larralde,
M.; Lebwohl, M.; Uitto, J.: Pseudoxanthoma elasticum is a recessive
disease characterized by compound heterozygosity. J. Invest. Derm. 126:
782-786, 2006.

54. Ringpfeil, F.; Pulkkinen, L.; Uitto, J.: Molecular genetics of
pseudoxanthoma elasticum. Exp. Derm. 10: 221-228, 2001.

55. Ross, R.; Fialkow, P. J.; Altman, L. K.: Fine structure alterations
of elastic fibers in pseudoxanthoma elasticum. Clin. Genet. 13:
213-223, 1978.

56. Sandberg, L. B.; Soskel, N. T.; Leslie, J. G.: Elastin structure,
biosynthesis, and relation to disease states. New Eng. J. Med. 304:
566-579, 1981.

57. Schon, S.; Schulz, V.; Prante, C.; Hendig, D.; Szliska, C.; Kuhn,
J.; Kleesiek, K.; Gotting, C.: Polymorphisms in the xylosyltransferase
genes cause higher serum XT-1 activity in patients with pseudoxanthoma
elasticum (PXE) and are involved in a severe disease course. J. Med.
Genet. 43: 745-749, 2006.

58. Strandberg, J.: Pseudoxanthoma elasticum. Z. Haut Geschlechtskr. 31:
689 only, 1929.

59. Struk, B.; Neldner, K. H.; Rao, V. S.; St Jean, P.; Lindpaintner,
K.: Mapping of both autosomal recessive and dominant variants of
pseudoxanthoma elasticum to chromosome 16p13.1. Hum. Molec. Genet. 6:
1823-1828, 1997.

60. van Soest, S.; Swart, J.; Tijmes, N.; Sandkuijl, L. A.; Rommers,
J.; Bergen, A. A. B.: A locus for autosomal recessive pseudoxanthoma
elasticum, with penetrance of vascular symptoms in carriers, maps
to chromosome 16p13.1. Genome Res. 7: 830-834, 1997.

61. Viljoen, D.: Pseudoxanthoma elasticum (Gronblad-Strandberg syndrome). J.
Med. Genet. 25: 488-490, 1988.

62. Viljoen, D. L.; Pope, F. M.; Beighton, P.: Heterogeneity of pseudoxanthoma
elasticum: delineation of a new form? Clin. Genet. 32: 100-105,
1987.

63. Zarbock, R.; Hendig, D.; Szliska, C.; Kleesiek, K.; Gotting, C.
: Vascular endothelial growth factor gene polymorphisms as prognostic
markers for ocular manifestations in pseudoxanthoma elasticum. Hum.
Molec. Genet. 18: 3344-3351, 2009.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Eyes];
Peau d'orange retinal changes (yellow-mottled retinal hyperpigmentation);
Angioid streaks of the retina (85% of patients);
Macular degeneration;
Visual impairment (50-70% of patients);
Central vision loss;
Colloid bodies;
Retinal hemorrhage;
Choroidal neovascularization;
Macular degeneration;
Optic head drusen (yellowish-white irregularities of optic disc);
Owl's eyes (paired hyperpigmented spots);
[Mouth];
Mucosal PXE lesions (inner aspect lower lip, cheeks, and palate)

CARDIOVASCULAR:
[Heart];
Congestive heart failure;
Calcifications (atrial and ventricular endocardium);
Mitral valve prolapse (uncommon);
Mitral valve stenosis (uncommon);
Restrictive cardiomyopathy (very rare);
[Vascular];
Accelerated atherosclerosis;
Coronary artery disease;
Angina pectoris;
Intermittent claudication (30%);
Renovascular hypertension (rare);
Absent peripheral pulses

ABDOMEN:
[Gastrointestinal];
Gastrointestinal hemorrhage

GENITOURINARY:
[Internal genitalia, female];
Uterine hemorrhage;
[Kidneys];
Renal failure;
[Bladder];
Bladder hemorrhage

SKIN, NAILS, HAIR:
[Skin];
Progression of skin lesions -;
1. yellowish, flat papules (neck, antecubital and popliteal fossae,
axillae, inguinal, and periumbilical areas);
2. yellowish, flat plaques;
3. lax, wrinkled skin;
Extrusion of calcium deposits ('perforating PXE');
Acneiform lesions (rare);
Chronic granulomatous nodules (rare);
Brown macules in a reticulate pattern (rare)

NEUROLOGIC:
[Central nervous system];
Stroke

MISCELLANEOUS:
Incidence - 1 in 25,000-100,000;
Sex ratio - 2 females to 1 male;
Majority of cases diagnosed at age 10-15 years;
See 177850 for description of heterozygous phenotype

MOLECULAR BASIS:
Caused by mutations in the ATP-binding cassette, subfamily C, member
6 gene (ABCC6, 603234.0001)

*FIELD* CN
Kelly A. Przylepa - updated: 10/12/2005
Kelly A. Przylepa - revised: 10/18/2001

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

*FIELD* ED
joanna: 10/12/2005
joanna: 3/14/2005
joanna: 10/18/2001

*FIELD* CN
Marla J. F. O'Neill - updated: 2/8/2012
Cassandra L. Kniffin - updated: 11/10/2010
George E. Tiller - updated: 7/7/2010
Cassandra L. Kniffin - updated: 3/25/2010
Cassandra L. Kniffin - updated: 10/14/2009
George E. Tiller - updated: 10/28/2008
Victor A. McKusick - updated: 3/6/2007
Victor A. McKusick - edited: 9/21/2005
Victor A. McKusick - updated: 5/11/2004
Victor A. McKusick - updated: 11/26/2003
Cassandra L. Kniffin - reorganized: 10/24/2003
Cassandra L. Kniffin - updated: 10/16/2003
Jane Kelly - updated: 8/22/2003
Gary A. Bellus - updated: 5/20/2003
Victor A. McKusick - updated: 2/22/2002
Ada Hamosh - updated: 5/22/2000
Victor A. McKusick - updated: 12/15/1999
Victor A. McKusick - updated: 7/1/1998
Victor A. McKusick - updated: 12/10/1997
Victor A. McKusick - updated: 11/4/1997
Victor A. McKusick - updated: 9/23/1997

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

*FIELD* ED
terry: 03/15/2013
alopez: 8/8/2012
carol: 2/29/2012
carol: 2/24/2012
carol: 2/8/2012
terry: 7/7/2011
terry: 3/14/2011
terry: 3/11/2011
terry: 3/10/2011
wwang: 11/15/2010
ckniffin: 11/10/2010
wwang: 7/20/2010
terry: 7/7/2010
wwang: 6/18/2010
ckniffin: 3/25/2010
wwang: 10/30/2009
ckniffin: 10/14/2009
terry: 3/24/2009
wwang: 10/28/2008
alopez: 3/13/2007
alopez: 3/9/2007
terry: 3/6/2007
terry: 2/16/2006
carol: 1/27/2006
carol: 1/24/2006
carol: 1/12/2006
joanna: 12/20/2005
alopez: 9/21/2005
tkritzer: 6/3/2004
terry: 5/11/2004
terry: 2/19/2004
tkritzer: 12/8/2003
tkritzer: 12/4/2003
terry: 11/26/2003
ckniffin: 10/27/2003
carol: 10/24/2003
ckniffin: 10/16/2003
carol: 8/22/2003
alopez: 5/20/2003
cwells: 3/13/2002
cwells: 3/7/2002
terry: 2/22/2002
carol: 6/14/2000
alopez: 5/22/2000
alopez: 12/21/1999
mcapotos: 12/17/1999
terry: 12/15/1999
carol: 10/12/1998
carol: 7/14/1998
dholmes: 7/13/1998
terry: 7/1/1998
mark: 12/17/1997
terry: 12/10/1997
mark: 11/19/1997
terry: 11/13/1997
terry: 11/4/1997
terry: 9/26/1997
terry: 9/23/1997
davew: 8/19/1994
mimadm: 5/17/1994
terry: 5/2/1994
pfoster: 4/22/1994
warfield: 4/19/1994
carol: 4/15/1994

MIM 603234
*RECORD*
*FIELD* NO
603234
*FIELD* TI
*603234 ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 6; ABCC6
;;ANTHRACYCLINE RESISTANCE-ASSOCIATED PROTEIN; ARA;;
read moreMULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 6; MRP6
*FIELD* TX

DESCRIPTION

ABCC6 belongs to the multidrug resistance-associated protein (MRP)
subfamily of ATP-binding cassette (ABC) transmembrane transporters. MRPs
are involved in drug resistance, particularly in association with cancer
chemotherapy. Mutations in the ABCC6 gene cause pseudoxanthoma elasticum
(PXE; see 264800), a heritable connective tissue disorder characterized
by calcification of elastic fibers in skin, arteries, and retina (Bergen
et al., 2000; Le Saux et al., 2000; Ringpfeil et al., 2000).

CLONING

Multidrug resistance in cancer cells has been attributed to the
overexpression of certain membrane proteins, several of which are
members of the ATP-binding cassette (ABC) superfamily. Examples include
MRP (158343) and MDR1 (171050). Longhurst et al. (1996) screened an
E1000 leukemia cell cDNA library using an MRP probe. They cloned a novel
cDNA encoding a 453-amino acid polypeptide that was similar to the
C-terminal half of MRP. Whereas MRP contains 2 ABC domains and 12
transmembrane domains, the ARA protein contains 1 ABC domain and 5
transmembrane domains. Northern blot analysis showed that ARA was
expressed as a 2.2-kb mRNA in an E1000 leukemia cell line, but not in
the untransformed parental CEM cell line. Southern blot analysis
revealed that, like MRP, the ARA gene was amplified in the genomic DNA
of the E1000 cell line. The ABCC6 protein consists of 1,503 amino acids
with a molecular mass of 165 kD, is located in the plasma membrane, and
probably has 17 membrane-spanning helices grouped into 3 transmembrane
domains (Le Saux et al., 2000). The 4.5-kb ABCC6 mRNA is expressed in
several secretory tissues, but primarily in kidney and liver. By RT-PCR
analysis using RNA isolated from tissues frequently affected by PXE,
Bergen et al. (2000) detected expression of ABCC6 in retina, skin, and
vascular tissue, although the highest level of expression was in the
liver.

By Western blot analysis of transfected Chinese hamster ovary (CHO)
cells, Belinsky et al. (2002) found that MRP6 migrated at the predicted
molecular mass of about 152 kD and at 182 kD, which likely represents a
glycosylated form.

Sinko et al. (2003) found that human ABCC6, when expressed by retroviral
transduction in polarized mammalian cells (MDCKII), is exclusively
localized to the basolateral membrane. In contrast to the in vitro
translated protein, ABCC6 was glycosylated in MDCK cells. Limited
proteolysis of the fully glycosylated and underglycosylated forms,
followed by immunodetection with region-specific antibodies, indicated
that asn15, located in the extracellular N-terminal region of ABCC6, is
the only N-glycosylated site in the protein.

By in situ hybridization and immunohistochemical analysis, Beck et al.
(2005) detected ABCC6 mRNA and protein in a wide range of epithelial
cells of exocrine and endocrine tissues such as acinar cells in the
pancreas, mucosal cells of the intestine, and follicular epithelial
cells of the thyroid. Enteroendocrine G cells of the stomach showed
strong immunostaining. In addition, ABCC6 mRNA and protein were present
in most neurons of the brain, in alveolar macrophages in the lung, in
lymph node lymphocytes, in hepatocytes, and in keratinocytes and
epithelial cells of the ducts of sweat glands.

Using PCR, Matsuzaki et al. (2005) found that Abcc6 expression was
highest in mouse liver and lower in kidney and small intestine.
Second-round nested PCR revealed much weaker expression in brain,
tongue, stomach, and eye. Subcloning and sequencing of distinct PCR
products indicated that the 3-prime end is subject to aberrant splicing,
resulting in each case in a premature termination codon. PCR analysis of
cultured human cells revealed similar splice variations in the 3-prime
end resulting in the skipping of exons 24 and 30 in epidermal
keratinocytes, and exons 24, 26, and 28 in dermal fibroblasts. In
fibroblasts, a minor PCR product represented alternative splicing of
exon 7.

GENE STRUCTURE

Kool et al. (1999) determined that the human ABCC6 gene comprises 31
exons.

Ratajewski et al. (2008) found that the 5-prime upstream region of the
ABCC6 gene contains a major Alu element of over 4.5 kb.

GENE FUNCTION

Belinsky and Kruh (1999) and Klein et al. (1999) suggested that ABCC6
function may be related to cellular detoxification rather than drug
resistance. Bergen et al. (2000) commented that the molecules presumably
transported by ABCC6 may be essential for extracellular matrix
deposition or turnover of connective tissue at specific sites in the
body. Given the high expression of ABCC6 in liver and kidney, ABCC6
substrates may be transported into the blood. A deficiency of specific
ABCC6 substrates may affect a range of connective tissue sites
throughout the body and specifically elastic fiber assembly.

By assaying membrane vesicles obtained from ABCC6-expressing insect
cells, Ilias et al. (2002) found ABCC6 specifically bound MgATP and
actively transported glutathione conjugates, including leukotriene-C4
and N-ethylmaleimide S-glutathione (NEM-GS), in an MgATP-dependent
manner. 17-Beta-estradiol-17-beta-D-glucuronide was a weak transport
substrate. The organic anions probenecid, benzbromarone, and
indomethacin specifically inhibited ABCC6-mediated NEM-GS transport, and
orthovanadate, a phosphotyrosine phosphatase inhibitor, completely
inhibited NEM-GS transport.

Using similar substrates, Belinsky et al. (2002) found that MRP6
expressed in CHO cell membranes could transport glutathione conjugates
but not glucuronate conjugates. Transfected cells also showed enhanced
resistance to several anticancer agents. The highest levels of
resistance were observed for the inhibitors of topoisomerase II (126430)
etoposide and teniposide, followed by the anthracyclines doxorubicin and
daunorubicin. MRP6-expressing CHO cells accumulated less etoposide
compared with control transfected cells, indicating that MRP6 functions
as a drug efflux pump.

Using a luciferase reporter gene construct, Jiang et al. (2006) examined
the 2.6-kb human ABCC6 promoter. An NF-kappa-B (see NFKB1, 164011)-like
sequence conferred strong expression in HepG2 hepatoma cells, but much
weaker expression in cell lines of other tissue origin. Injection of the
construct into mouse tail vein confirmed liver-specific expression.
Testing of selected cytokines revealed that TGF-beta (190180)
upregulated, while TNF-alpha (191160) and interferon-gamma (IFNG;
147570) downregulated, the promoter activity in HepG2 cells. The
responsiveness to TGF-beta resided primarily within an SP1 (189906)/SP3
(601804) binding site. The expression of the ABCC6 promoter was markedly
enhanced by SP1. Jiang et al. (2006) concluded that the expression of
ABCC6 can be modulated by proinflammatory cytokines.

Using the ABCC6 promoter region in reporter gene assays in the HepG2
hepatoma cell line, Ratajewski et al. (2006) showed that all-trans
retinoic acid caused significant induction of ABCC6 activity. They found
9-cis retinoic acid (9cRA), a specific RXR (see RXRA, 180245) receptor
agonist, induced the ABCC6 promoter in a concentration-dependent manner.
9cRA also induced the expression of endogenous ABCC6 in HepG2 cells. The
binding of RXR to the endogenous ABCC6 promoter was confirmed by
chromatin immunoprecipitation experiments. Occupancy of the ABCC6
promoter by RXR was relatively high in unstimulated cells and increased
further in 9cRA-treated cells.

Using the ABCC6 reporter construct described by Ratajewski et al. (2006)
in a screen for ABCC6-regulating factors, Ratajewski et al. (2008) found
that GATA3 (131320) repressed ABCC6 activity, and that SP1, PLAG1
(603026), and PLAGL1 (603044) induced ABCC6 activity. They identified 2
putative PLAG-binding sites on the reverse strand of the ABCC6 proximal
promoter. Reporter gene assays, electrophoretic mobility shift assays,
and chromatin immunoprecipitation analysis showed that the more proximal
site was bound and activated by PLAG1 and PLAGL1. Furthermore,
overexpression of PLAG1 resulted in enhanced ABCC6 transcription in
transfected human embryonic kidney cells.

MAPPING

Kuss et al. (1998) used fluorescence in situ hybridization to map the
ARA gene to human chromosome 16p13.1. The gene order in this region is
telomere--MYH11(160745)--MRP--ARA--centromere. The MRP and ARA genes are
located within 9 kb of each other and are transcribed in opposite
directions. Both MRP and ARA are deleted in a subgroup of inv(16)
leukemias, and both are expressed in normal hematopoietic precursor
cells.

- Pseudogenes

Pulkkinen et al. (2001) identified 2 pseudogenes containing sequences
highly homologous to the 5-prime end of the ABCC6 gene.

MOLECULAR GENETICS

- Pseudoxanthoma Elasticum

Simultaneously and independently, Bergen et al. (2000), Le Saux et al.
(2000), and Ringpfeil et al. (2000) identified missense, nonsense, and
splice site mutations as well as deletions and insertions in the ABCC6
gene accounting for pseudoxanthoma elasticum (264800). Mutations
appeared to represent autosomal recessive (Le Saux et al., 2000) and
autosomal dominant (177850) (Bergen et al., 2000) modes of inheritance,
and sporadic cases. By SSCP and heteroduplex analysis using genetic DNA
from a cohort of 17 unrelated PXE patients, Le Saux et al. (2000)
screened 109 exons within 5 PXE candidate genes in the chromosome
16p13.1 region for mutations. By screening the 31 exons of ABCC6 by
SSCP, Le Saux et al. (2000) identified 6 mutations that were responsible
for PXE in 10 of 17 patients. They identified a C-to-T substitution
within exon 24 at nucleotide 3421, resulting in an arg-to-stop
substitution at codon 1141 (R1141X; 603234.0001) in 6 unrelated families
with autosomal recessive PXE. Bergen et al. (2000) identified mutations
in ABCC6 causing autosomal dominant, autosomal recessive, and sporadic
PXE. Bergen et al. (2000) found the R114X mutation in 2 families with
autosomal dominant PXE. One patient had a large de novo deletion of
chromosome 16 (603234.0010). Ringpfeil et al. (2000) reported a total of
8 pathogenetic mutations in the ABCC6 gene in 8 kindreds with PXE. They
referred to the gene as MRP6 (multidrug resistance-associated
protein-6). Examination of clinically unaffected family members in 4
multiplex families identified heterozygous carriers, consistent with an
autosomal recessive inheritance pattern.

Le Saux et al. (2001) performed a mutation analysis of the ABCC6 gene in
122 unrelated patients with PXE, the largest cohort of patients studied
to that time. They characterized 36 mutations, 28 of which were novel.
Twenty-one were missense variants, 6 were small insertions or deletions,
5 were nonsense, 2 were alleles likely to result in aberrant mRNA
splicing, and 2 were large deletions involving ABCC6. Although most
mutations appeared to be unique variants, 2 disease-causing alleles
occurred frequently in apparently unrelated individuals. Arg1141 to ter
(R1141X; 603234.0001) was found in this patient cohort at a frequency of
18.8% and was preponderant in European patients. Deletion of nucleotides
23-29 (603234.0016) occurred at a frequency of 12.9% and was prevalent
in patients from the United States. Putative disease-causing mutations
were identified in approximately 64% of the 244 chromosomes studied, and
85.2% of the 122 patients were found to have at least 1 disease-causing
allele. The results suggested that a fraction of the undetected mutant
alleles could be either genomic rearrangements or mutations occurring in
noncoding regions of the ABCC6 gene. A cluster of disease-causing
variants was observed within exons encoding a large C-terminal
cytoplasmic loop and in the C-terminal nucleotide-binding domain.

While implementing a strategy to screen for PXE by complete mutation
analysis of the ABCC6 gene, Germain (2001) found evidence for the
existence of at least 1 pseudogene highly homologous to the 5-prime end
of ABCC6. Sequence variants in this ABCC6-like pseudogene could be
mistaken for mutations in the ABCC6 gene and consequently lead to
erroneous genotyping results in pedigrees affected with PXE.

Germain et al. (2001) identified a heterozygous missense mutation in
exon 7 of the ABCC6 gene in a female PXE patient whose parents were
second cousins. Despite complete scanning of the gene, no further
mutation was evident. A heterozygous profile was also found in the
proband's unaffected children. However, haplotype homozygosity was
confirmed at chromosome 16p13.1, using both extragenic microsatellites
and intragenic polymorphisms located 3-prime from the mutation, in
agreement with the known consanguinity in the family. Taken together,
the data indicated that PCR products of exon 7 of the ABCC6 gene were
amplified from more than 2 genomic copies. This supported the existence
of one or more ABCC6 pseudogenes highly homologous to the 5-prime end
(exons 1-9) of the ABCC6 gene.

Pulkkinen et al. (2001) identified 2 pseudogenes containing sequences
highly homologous to the 5-prime end of the ABCC6 gene. Nucleotide
differences in flanking introns between these 2 pseudogenes and ABCC6
allowed them to design allele-specific primers that eliminated the
amplification of both pseudogene sequences by PCR and provided reliable
amplification of ABCC6-specific sequences only. The use of
allele-specific PCR revealed 2 novel 5-prime-end PXE mutations.

In 59 unrelated Dutch patients with PXE, Hu et al. (2003) identified 17
different mutations, including 11 novel mutations, in the ABCC6 gene in
65 alleles. The R1141X mutation was by far the most common mutation,
identified in 19 (32.2%) patients; the second most common mutation,
which results in the deletion of exons 23-29 (603234.0014), was
identified in 11 (18.6%) patients. In 20 patients, only 1 mutation in 1
allele was detected. Combined with previous mutation data, Hu et al.
(2003) concluded that approximately 80% of the PXE mutations occur in
the cytoplasmic domains of the predicted ABCC6 protein, especially the 2
nucleotide-binding fold (NBF) domains (NBF1 and NBF2) and the eighth
cytoplasmic loop between the fifteenth and sixteenth transmembrane
regions.

Hu et al. (2004) described an efficient molecular diagnostic strategy
for ABCC6 in PXE. The 2 most frequent mutations, R1141X (603234.0001)
and deletion of exons 23 through 29 (603234.0016), as well as a core set
of mutations, were identified by restriction enzyme digestion and size
separation on agarose gels. In the remaining patient group in which only
1 or no mutant allele was found, the complete coding sequence was
analyzed using DHPLC. All variations found were confirmed by direct DNA
sequencing. Finally, Southern blot was used to investigate the potential
presence of small or large deletions. Twenty different mutations,
including 2 novel mutations in the ABCC6 gene, were identified in 80.3%
of the 76 patients, and 58.6% of the 152 ABCC6 alleles analyzed.

Chassaing et al. (2005) commented that mutations had been identified in
PXE in most of the 31 ABCC6 exons and that no correlation between the
nature or the location of the mutations and phenotype severity had been
established.

Trip et al. (2002), Van Soest et al. (1997), and Bacchelli et al. (1999)
emphasized the carriage of a sole ABCC6 mutation as a cardiovascular
risk factor. Sherer et al. (2001) described limited phenotypic
expression of PXE in parents of affected offspring.

Miksch et al. (2005) performed a mutation screen in ABCC6 using
haplotype analysis in conjunction with direct sequencing to achieve a
mutation detection rate of 97%. Their mutational analysis confirmed an
earlier haplotype-based analysis and conclusions regarding a
recessive-only mode of inheritance in PXE (Cai et al., 2000) through the
identification of 2 mutated alleles in all individuals with PXE who
appear in either consecutive or alternating generations of the same
family. Their study demonstrated that the full phenotypic expression of
the disorder requires 2 defective allelic copies of ABCC6 and that
pseudodominance is the mode of transmission in presumed autosomal
dominant families (i.e., the second parental disease allele 'marries
into' the family). The apparent frequency of this mechanism was
approximately 7.5% in their family cohort. Miksch et al. (2005) stated
that in their families no heterozygote for a large deletion showed any
apparent clinical sign of PXE according to category I diagnostic
criteria.

Chassaing et al. (2005) provided a comprehensive catalog of ABCC6
mutations identified in PXE.

Pfendner et al. (2007) collected mutation data on an international case
series of 270 patients with PXE (239 probands, 31 affected family
members). In 134 patients with a known phenotype and both mutations
identified, genotype-phenotype correlations were assessed. In total, 316
mutant alleles in ABCC6, including 39 novel mutations, were identified
in 239 probands. Mutations clustered in exons 24 and 28, corresponding
to the second nucleotide-binding fold and the last intracellular domain
of the protein. Together with the recurrent R1141X (603234.0001) and
del23-29 (603234.0016) mutations, these mutations accounted for 71.5% of
the total individual mutations identified. Genotype-phenotype analysis
failed to reveal a significant correlation between the type of mutations
identified or their predicted effect on the expression of the protein
and the age of onset and severity of the disease.

Using multiplex ligation-dependent probe amplification (MLPA) to analyze
35 PXE patients with incomplete ABCC6 genotypes after exonic sequencing,
Costrop et al. (2010) identified 6 multiexon deletions and 4 single-exon
deletions and were thus able to characterized 25% of the unidentified
disease alleles. The findings illustrated the instability of the ABCC6
genomic region and stressed the importance of screening for deletions in
the molecular diagnosis of PXE.

- Generalized Arterial Calcification of Infancy 2

In a 28-year-old French man with PXE, who had a younger brother who died
of generalized arterial calcification of infancy (GACI1; 614473) at age
15 months, Le Boulanger et al. (2010) identified compound heterozygosity
for missense mutations in the ABCC6 gene (603234.0025 and 603234.0026),
which were also found in heterozygosity in each of his unaffected
parents, respectively. No disease-causing mutations were found in the
known GACI1 (208000)-related gene, ENPP1 (173335). Although no DNA
material was available from the deceased younger brother, his disease
was presumed to be related to the familial ABCC6 mutations. Le Boulanger
et al. (2010) concluded that GACI may represent an atypical and severe
end of the vascular phenotypic spectrum of PXE.

Nitschke et al. (2012) analyzed the ABCC6 gene in 28 GACI patients from
25 unrelated families who were negative for mutation in the ENNP1 gene,
as well as 2 unrelated GACI patients in whom only 1 ENNP1 mutation had
been detected. They identified homozygosity or compound heterozygosity
for mutations in ABCC6 in 8 unrelated GACI patients (see, e.g.,
603234.0001, 603234.0006, and 603234.0027-603234.0029). In 6 patients
from 5 unrelated families, only 1 mutation was detected in ABCC6; the
authors noted that there was no phenotypic difference between these
patients and those with biallelic mutations in ABCC6, and stated that
mutations in regulatory untranslated regions of ABCC6 might not have
been detected by their approach. No mutation in the ABCC6 gene was found
in 16 patients from 14 unrelated families, including the 2 patients who
were known to carry monoallelic mutations in ENNP1. Overall, 13
different ABCC6 mutations were identified in GACI patients, all but 2 of
which had been previously identified in typical PXE patients who had a
much milder phenotype than the GACI patients. Based on the considerable
overlap of phenotype and genotype of GACI and pseudoxanthoma elasticum,
Nitschke et al. (2012) suggested that GACI and PXE represent 2 ends of a
clinical spectrum of ectopic calcification and other organ pathologies
rather than 2 distinct disorders.

POPULATION GENETICS

The Afrikaner population of South Africa is of Dutch, German, and French
Huguenot descent and has its origin in the first European immigrant
settlements at the Cape of Good Hope during the 17th century. Torrington
and Viljoen (1991) proposed that the basis for the high prevalence of
PXE in the Afrikaner population is a founder effect. An initial
genealogic study traced the ancestry of 20 Afrikaner families with PXE
back to potentially only 4 individuals, suggesting that this disorder is
most likely derived from these original founders in South Africa. To
further study this possibility, Le Saux et al. (2002) performed
haplotype and mutation analyses in 17 of the 20 originally analyzed
Afrikaner families, and identified 3 common haplotypes and 6 different
disease-causing variants. Three of these mutant alleles were missense
variants, 2 were nonsense mutations, and 1 was a single-basepair
insertion. The most common variant, arg1339 to cys (R1339C;
603234.0017), accounted for 53% of the PXE alleles, whereas other mutant
alleles appeared at lower frequencies ranging from 3 to 12%. Haplotype
analysis of the Afrikaner families showed that the 3 most frequent
mutations were identical by descent, indicating a founder origin of PXE
in this population.

Chassaing et al. (2005) suggested that the proposed prevalence of PXE of
1 in 25,000 may be an underestimation. Consequently, the prevalence of
heterozygous carriers, and the prevalence of different organ involvement
in carriers of 1 or 2 ABCC6 mutations, are not precisely known.

PATHOGENESIS

Since the ABCC6 gene is expressed primarily, if not exclusively, in the
liver and kidneys, Ringpfeil et al. (2001) suggested that PXE is a
primary metabolic disorder with secondary involvement of elastic fibers,
a situation comparable to the secondary involvement of connective tissue
elements in homocystinuria (236200) and alkaptonuria (203500).

ABCC6 is a member of the large ATP-dependent transmembrane transporter
family. Chassaing et al. (2005) commented that the association of PXE to
ABCC6 efflux transport alterations raised a number of pathophysiology
hypotheses, among them, the idea that PXE is a systemic metabolic
disease resulting from lack or accumulation over time in the bloodstream
of molecules interacting with the synthesis, turnover, and/or
maintenance of extracellular matrix (ECM).

Since ABCC6 is expressed primarily in the liver, Jiang and Uitto (2006)
likewise supported the notion that PXE is a metabolic disease.

In an investigation of the functional relationship between ABCC6
deficiency and elastic fiber calcification, Le Saux et al. (2006)
speculated that ABCC6 deficiency in PXE patients induces a persistent
imbalance in circulating metabolite(s) which impairs the synthetic
abilities of normal elastoblasts or specifically alters elastic fiber
assembly. They found that PXE fibroblasts cultured with normal human
serum expressed and deposited increased amounts of proteins, but
structurally normal elastic fibers. Normal and PXE fibroblasts as well
as normal smooth muscle cells deposited abnormal aggregates of elastic
fibers when maintained in the presence of serum from PXE patients. The
expression of tropoelastin (see 130160) and other elastic
fiber-associated genes was not significantly modulated by the presence
of PXE serum. These results indicated that certain metabolites present
in PXE sera interfered with the normal assembly of elastic fibers in
vitro and suggested that PXE is a primary metabolic disorder with
secondary connective tissue manifestations.

ANIMAL MODEL

To elucidate the pathogenesis of PXE, Klement et al. (2005) generated a
transgenic mouse by targeted ablation of the mouse Abcc6 gene.
Abcc6-null mice were negative for expression of Mrp6 in the liver, and
necropsies revealed profound mineralization of several tissues including
skin, arterial blood vessels, and retina, while heterozygous animals
were indistinguishable from the wildtype mice. Particularly striking was
the mineralization of vibrissae, as confirmed by von Kossa and alizarin
red stains. Electron microscopy revealed mineralization affecting both
elastic structures and collagen fibers. Mineralization of vibrissae was
noted as early as 5 weeks of age and was progressive with age in Abcc6
-/- mice but was not observed in heterozygous or wildtype mice up to 2
years of age. Total body computerized tomography scan of Abcc6 -/- mice
showed mineralization in skin and subcutaneous tissue as well as in
kidneys. These data demonstrated aberrant mineralization of soft tissues
in PXE-affected organs, and consequently, these mice recapitulated
features of this complex disease.

Gorgels et al. (2005) generated Abcc6 -/- mice and showed by light and
electron microscopy that Abcc6 -/- mice spontaneously developed
calcification of elastic fibers in blood vessel walls and in Bruch
membrane in the eye. No clear abnormalities were seen in the dermal
extracellular matrix. Calcification of blood vessels was most prominent
in small arteries in the cortex of the kidney, but in old mice, it
occurred also in other organs and in the aorta and vena cava. Monoclonal
antibodies against mouse Abcc6 localized the protein to the basolateral
membranes of hepatocytes and the basal membrane in renal proximal
tubules, but failed to show the protein at the pathogenic sites. Abcc6
-/- mice developed a 25% reduction in plasma HDL cholesterol and an
increase in plasma creatinine levels, which may be due to impaired
kidney function. No changes in serum mineral balance were found. Gorgels
et al. (2005) concluded that the phenotype of the Abcc6 -/- mouse shares
calcification of elastic fibers with human PXE pathology, and supports
the hypothesis that PXE is a systemic disease.

To characterize the mineralization process in PXE, Jiang et al. (2007)
examined a PXE animal model, the Abcc6 -/- mouse, with respect to
specific proteins serving as inhibitors of mineralization. The levels of
calcium and phosphate in serum of these mice were normal, but the Abcc6
-/- serum had less ability to prevent the mineral deposition induced by
inorganic phosphate in a cell culture system. Addition of fetuin-A
(138680) to the culture system prevented the mineralization. The
calcium-phosphate product was markedly elevated in the mineralized
vibrissae of Abcc6 -/- mice, an early biomarker of the mineralization
process, consistent with histopathologic findings. Levels of fetuin-A
were slightly decreased in Abcc6 -/- serum, and positive immunostaining
for matrix-Gla-protein (MGP; 154870), fetuin-A, and ankylosis protein
(ANK; 605145) as well as alkaline phosphatase activity were strongly
associated with the mineralization process. In situ hybridization
demonstrated that the genes for MGP and Ank were expressed locally in
vibrissae, whereas fetuin-A was expressed highly in the liver. These
data suggested that the deposition of the bone-associated proteins
spatially coincides with mineralization and actively regulates this
process locally and systemically.

In the Dyscalc1 mouse model of dystrophic cardiac calcification (DCC),
Meng et al. (2007) studied 2 intercrosses and identified Abcc6 as the
causative gene, which was confirmed by transgenic complementation. The
authors noted that myocardial calcification has not been reported as a
phenotype associated with human PXE or mouse Abcc6-knockout models.

In all mouse strains positive for DCC, Aherrahrou et al. (2008)
identified a missense mutation at the 3-prime border of exon 14 of the
Abcc6 gene that created an additional donor splice site. The alternative
transcript lacked the last 5 nucleotides of exon 14, resulting in
premature termination at codon 684, and leading to Abcc6 protein
deficiency in DCC-susceptible mice.

Jiang et al. (2009) found that grafting of wildtype mouse muzzle skin
onto the back of Abcc6-knockout mice resulted in abnormal mineralization
of vibrissae consistent with PXE, whereas grafting of Abcc6-knockout
mouse muzzle skin onto wildtype mice did not. The data implied that PXE
does not result from localized defect based on resident cellular
abnormalities but from a change of metabolite(s) in serum. These
findings implicate circulatory factors as a critical component of the
mineralization process and supported the notion that PXE is a secondary
mineralization of connective tissues. In addition, the findings
suggested that the abnormal mineralization process could possibly be
countered or even reversed by changes in the homeostatic milieu.

*FIELD* AV
.0001
PSEUDOXANTHOMA ELASTICUM
ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2, INCLUDED
ABCC6, ARG1141TER

---Pseudoxanthoma Elasticum

In a large consanguineous Italian family segregating autosomal recessive
pseudoxanthoma elasticum (264800), Le Saux et al. (2000) identified a
C-to-T transition at nucleotide 3421 in exon 24 of the ABCC6 gene,
resulting in an arg-to-ter substitution at codon 1141 (R1141X). All
unaffected individuals but 1 were heterozygous carriers; affected
individuals were homozygous for this mutation. This variant was not
found in the control panel of 200 normal alleles and cosegregated in
homozygous or compound heterozygous state with the PXE phenotype in
families. This mutation was also identified in 5 unrelated pedigrees.
R1141X was found in homozygous state in unrelated patients with
autosomal recessive PXE from the United Kingdom and Belgium. Haplotype
analysis of the PXE locus in families with the R1141X mutation revealed
that this mutation was segregating with different haplotypes, suggesting
that R1141X may be a recurrent mutation in ABCC6. Testing of cultured
skin fibroblasts showed no ABCC6 mRNA in patients carrying the R1141X
mutation from the large Italian pedigree.

Bergen et al. (2000) identified this mutation in 2 families segregating
autosomal dominant PXE (177850).

In a family in which 2 brothers and a sister had PXE, Ringpfeil et al.
(2000) demonstrated that the affected individuals were compound
heterozygotes for the R1141X mutation and an R1268Q mutation
(603234.0011).

In a cohort of 101 unrelated patients with PXE, Le Saux et al. (2001)
found that the R1141X mutant allele was present in 28.4% of European
alleles and only 4.1% of U.S. alleles. Also, this nonsense mutation was
unequally distributed among European countries. The frequency of
homozygotes was in Hardy-Weinberg equilibrium in the European
population.

Hu et al. (2003) demonstrated a founder effect for the R1141X mutation
in the Netherlands. They identified the mutation in 19 alleles in 16
Dutch patients with PXE, in heterozygous, homozygous, or compound
heterozygous form. Expression of the normal allele in heterozygotes was
predominant; no or very low expression was found in homozygotes. The
mutation induced instability of the aberrant mRNA. Hu et al. (2003)
suggested that the PXE phenotype of the R1141X mutation most likely
results from complete loss of function or functional haploinsufficiency
of ABCC6.

In the study of Trip et al. (2002), the presence of a single R1141X
mutation in ABCC6 appeared to be an independent risk factor for coronary
heart disease in young people.

---Generalized Arterial Calcification of Infancy 2

In 2 patients with generalized arterial calcification of infancy-2
(GACI2; 614473), Nitschke et al. (2012) identified compound
heterozygosity for 2 mutations in the ABCC6 gene. A French female infant
with GACI who died at 6 weeks of age, who had calcification of the
coronary arteries and other arteries, severe hypertension, and heart
failure, was compound heterozygous for R1141X and R1314W (603234.0006).
A 3-year-old Spanish boy with GACI who had calcification of the splenic
and pancreatic arteries, nephrocalcinosis, severe hypertension,
cardiomegaly, psychomotor retardation, and abdominal distention, was
compound heterozygous for R1141X and R518X (603234.0027).

---Pseudoxanthoma Elasticum, Forme Fruste, Digenic, ABCC6/GGCX

In a woman and her sister with biopsy-confirmed PXE, Li et al. (2009)
identified compound heterozygosity for the R1141X mutation and a
mutation in the GGCX gene (V255M; 137167.0012). Neither had evidence of
a coagulopathy and the skin phenotype was mild (see 177850), but skin
biopsies showed undercarboxylated matrix gla proteins (MGP; 154870) in
the areas of abnormal mineralization. Since R1141X in the heterozygous
state is usually not associated with clinical features, the findings
suggested that the women had digenic inheritance of PXE. In contrast, 2
other family members who were compound heterozygous for R1141X and
another mutation in the GGCX gene (S300F; 137167.0013) had no signs of
either disorder on clinical exam but refused further clinical testing.
Plasma levels of undercarboxylated total MGP of the 2 clinically
unaffected individuals were at the lower end of normal. Although the
reasons for the lack of clinical findings in the 2 unaffected family
members remained unclear, Li et al. (2009) concluded that
undercarboxylation of MGP plays a critical role in aberrant
mineralization of tissues in PXE.

.0002
PSEUDOXANTHOMA ELASTICUM
ABCC6, IVS21, G-T, +1

In patients with autosomal recessive pseudoxanthoma elasticum (264800)
from 2 families, Le Saux et al. (2000) found that affected individuals
carried a G-to-T transversion at the +1 position of intron 21 of the
ABCC6 gene, affecting the donor splice site. One of the families was
from the U.K., and the other was from the United States. The family from
the U.K. carried the R1141X mutation (603234.0001) on the other allele;
in the American family, the other mutation was R1138Q (603234.0003).

.0003
PSEUDOXANTHOMA ELASTICUM
ABCC6, ARG1138GLN

In a family with autosomal recessive pseudoxanthoma elasticum (264800),
Le Saux et al. (2000) identified a G-to-A transition at nucleotide 3413
of the ABCC6 gene, resulting in an arginine-to-glutamine substitution at
codon 1138 (R1138Q). This mutation was found in compound heterozygosity
with the IVS21+1G-T mutation (603234.0002).

In a so-called sporadic case of PXE, Ringpfeil et al. (2000) identified
an R1138Q mutation in the ABCC6 gene in compound heterozygosity with the
R1268 mutation (603234.0011). Arginine-1138 is the same codon as that
affected in the R1138W mutation (603234.0012); in the latter mutation,
the nucleotide change is 3412C-T.

.0004
PSEUDOXANTHOMA ELASTICUM
ABCC6, ARG1114PRO

In a family with autosomal recessive pseudoxanthoma elasticum (264800),
Le Saux et al. (2000) found affected individuals to be homozygous for a
G-to-C transversion at nucleotide 3341 of the ABCC6 gene, resulting in
an arg-to-pro substitution at codon 1114 (R1114P) in exon 24. This
mutation was found in homozygosity.

.0005
PSEUDOXANTHOMA ELASTICUM
ABCC6, 1-BP DEL, 3775T

In a patient thought to represent an isolated case of autosomal dominant
pseudoxanthoma elasticum (177850), Le Saux et al. (2000) found a
deletion of a T at nucleotide 3775 of the ABCC6 gene. This was a de novo
mutation in the patient, and no mutations were found in the other allele
of ABCC6 by screening using SSCP.

Plomp et al. (2009) examined a group of 15 adults homozygous for the
3775delT mutation and 44 individuals heterozygous for this mutation from
a genetically isolated population in the Netherlands. All participants
filled out a questionnaire and underwent standardized dermatologic and
ophthalmologic examinations with photography of skin and fundus
abnormalities. Skin biopsies from affected skin or a predilection site
and/or a scar were examined and compared with biopsies from controls.
Plomp et al. (2009) found that skin abnormalities, ophthalmologic signs,
and cardiovascular problems varied greatly among the 15 homozygous
participants. There was no correlation among severity of skin, eyes, or
cardiovascular abnormalities. None of the 44 heterozygous participants
had any sign of pseudoxanthoma elasticum on dermatologic,
histopathologic, and/or ophthalmologic examination, but 32% had
cardiovascular disease.

.0006
PSEUDOXANTHOMA ELASTICUM
ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2, INCLUDED
ABCC6, ARG1314TRP

Pseudoxanthoma Elasticum

In a patient with autosomal recessive pseudoxanthoma elasticum (264800),
Le Saux et al. (2000) identified a C-to-T transition at nucleotide 3940
of the ABCC6 gene, resulting in an arg-to-trp substitution at codon 1314
(R1314W). This mutation was found in homozygosity in one family.

Generalized Arterial Calcification of Infancy 2

In a 5-year-old boy with generalized arterial calcification of infancy
(GACI2; 614473), Nitschke et al. (2012) identified homozygosity for the
R1314W mutation. The boy was born as the first of dizygotic twins, and
his twin brother was unaffected. The patient had calcification of the
aorta and pulmonary, coronary, and renal arteries as well as other
arteries, and stippled calcifications of proximal epiphyses of humeri,
femora, pelvic cartilage, larynx, and mandible. He had severely
decreased biventricular systolic function, marked cardiomegaly, and
severe mitral insufficiency, as well as hypertension and respiratory
insufficiency. Cerebral MRI revealed diffuse white matter disease, with
cystic encephalomalacia, and laboratory analysis showed
hyperbilirubinemia, anemia, and thrombocytopenia. Nitschke et al. (2012)
also identified the R1314W mutation in compound heterozygosity in 2
unrelated GACI patients, a French female infant who died at 6 weeks of
age and also carried an R1141X mutation (603234.0001), and an
Afro-Caribbean male infant who died at 8 weeks of age with generalized
arterial stenosis, myocardial infarction, and hypertension and also
carried a 1-bp insertion (450insC; 603234.0028) in exon 4 of the ABCC6
gene, predicted to result in a premature stop codon and a truncated
protein. In addition, in a 3-year-old South African girl with GACI,
Nitschke et al. (2012) identified only a heterozygous R1314W mutation,
but noted that mutations in regulatory untranslated regions of ABCC6
might not have been detected by their technique. In the South African
child, onset of symptoms occurred at 2.5 years of age, and included
calcification of the aorta, spleen, and pancreas, nephrocalcinosis,
failure to thrive, hypertension, and heart failure.

.0007
PSEUDOXANTHOMA ELASTICUM
ABCC6, 1-BP DEL, 3798T

In a large autosomal recessive pseudoxanthoma elasticum (264800) family,
Bergen et al. (2000) identified the deletion of a T at nucleotide 3798
of the ABCC gene in homozygosity. This mutation results in a frameshift
and premature chain termination.

.0008
PSEUDOXANTHOMA ELASTICUM
ABCC6, 4-BP INS, 4243AGAA

In 2 families segregating what was thought to be autosomal dominant
pseudoxanthoma elasticum (177850), Bergen et al. (2000) identified a
4-bp insertion, AGAA, at nucleotide 4243 in exon 30. This insertion
causes a frameshift resulting in the disruption of the Walker B motif
and a protein longer by 24 amino acids.

.0009
PSEUDOXANTHOMA ELASTICUM
ABCC6, 22-BP DEL

In a patient with pseudoxanthoma elasticum (177850), Bergen et al.
(2000) identified a 22-basepair deletion from nucleotides 1967 through
1989 of the ABCC6 gene in heterozygosity. The other allele appeared to
be wildtype.

.0010
PSEUDOXANTHOMA ELASTICUM
ABCC6, DEL

In a patient with pseudoxanthoma elasticum (177850), Bergen et al.
(2000) detected a large deletion encompassing the ABCC6 gene as well as
the MYH11 (160745) and ABCC1 (158343) genes. The other allele appeared
to be wildtype.

.0011
PSEUDOXANTHOMA ELASTICUM
ABCC6, ARG1268GLN

Ringpfeil et al. (2000) found an arg1268-to-gln (R1268Q) mutation in
compound heterozygous state in 3 presumably unrelated families with PXE
(264800). In 2 families, the mutation was combined with R1141X
(603234.0001); in 1 family, it was combined with R1138Q (603234.0003).

In one of the families with PXE in which the R1141X mutation had been
identified by Ringpfeil et al. (2000), Germain et al. (2000) identified
a 3803G-A transition in exon 27 of the ABCC6 cDNA, resulting in an
R1268Q mutation. To their surprise, the R1268Q variant was found in
homozygous state in the proband's unaffected husband. They investigated
the R1268Q mutation and found the Q1268 allele at a relatively high
frequency (0.19) in a control population of 62 Caucasians. Genotype
frequencies were in Hardy-Weinberg equilibrium, and 3 healthy volunteers
were homozygous for the Q1268 allele. R1268Q is thus a harmless
polymorphism when present in homozygous state.

.0012
PSEUDOXANTHOMA ELASTICUM
ABCC6, ARG1138TRP

In a familial case of PXE (264800), Ringpfeil et al. (2000) found
homozygosity for an arg1138-to-trp (R1138W) mutation in the ABCC6 gene
due to a 3412C-T transition. The mutation was found in homozygous state
in the proband's mother and in heterozygous state in her father,
creating a pedigree pattern of pseudodominance. The same codon is
involved in the R1138Q mutation due to a 3413G-A transition
(603234.0003).

Ringpfeil et al. (2001) discussed the same pedigree, derived from a
consanguineous French-Canadian PXE family.

.0013
PSEUDOXANTHOMA ELASTICUM
ABCC6, ARG1164TER

Ringpfeil et al. (2001) studied the ABCC6 mutation in 4 multiplex
families with PXE (264800) inherited in an autosomal recessive pattern.
In each family, the proband was a compound heterozygote for a single-bp
substitution mutation (3490C-T; arg1164 to ter) and a novel deletion of
approximately 16.5 kb spanning the site of the single-bp substitution in
trans (i.e., on the homologous chromosome 16) (603234.0014). In 2 of the
families the single-nucleotide substitution was R1164X; in 1 it was
R1141X (603234.0001); and in another it was a splice site mutation,
3736-1G-A (603234.0015). In all 4 families the patients were thought
first to be homozygous for the nondeletion mutation. The deletion
mutation was shown to extend from intron 22 to intron 29, resulting in
out-of-frame deletion of 1,213 nucleotides from the corresponding mRNA
and causing elimination of 505 amino acids from the MRP6 polypeptide.
The deletion breakpoints were precisely the same in all 4 families,
which were of different ethnic backgrounds, and haplotype analysis by 13
microsatellite markers suggested that the deletion had occurred
independently. Deletion breakpoints within introns 22 and 29 were
embedded within AluSx repeat sequences, specifically in a 16-bp segment
of DNA, suggesting Alu-mediated homologous recombination as a mechanism.

.0014
PSEUDOXANTHOMA ELASTICUM
ABCC6, 1,213-NT DEL

See 603234.0013 and Ringpfeil et al. (2001).

.0015
PSEUDOXANTHOMA ELASTICUM
ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2, INCLUDED
ABCC6, IVS26, G-A, -1

See 603234.0013 and Ringpfeil et al. (2001).

See 603234.0029 and Nitschke et al. (2012).

.0016
PSEUDOXANTHOMA ELASTICUM
ABCC6, EX23-29DEL

In a cohort of 101 unrelated patients with PXE (264800), Le Saux et al.
(2001) identified a 16.4-kb deletion of the ABCC6 gene (deletion of
exons 23-29) in 12.9% of mutant alleles. The frequency was very
different in Europe and the United States, being 4.3% and 28.4%,
respectively. The frequency of individuals homozygous for this mutation
was observed to be in Hardy-Weinberg equilibrium in the United States.

.0017
PSEUDOXANTHOMA ELASTICUM
ABCC6, ARG1339CYS

In 17 Afrikaner families in South Africa with autosomal recessive
pseudoxanthoma elasticum (264800), Le Saux et al. (2002) found that 53%
of the PXE-associated alleles of the ABCC6 gene had a 4015C-T
transition, which caused an arg1339-to-cys (R1339C) mutation. Haplotype
analysis showed that the mutation was identical by descent in these
families.

.0018
PSEUDOXANTHOMA ELASTICUM
ABCC6, ARG1459CYS

In a family in which PXE classified as 'definite' occurred in 2
generations, Plomp et al. (2004) detected an arg1459-to-cys substitution
(R1459C) in the ABCC protein on 1 allele only. The authors considered
the diagnosis of PXE definite if 2 of the following 3 criteria were
present: yellowish papules and/or plaques on the lateral side of the
neck and/or flexural areas of the body; typical histopathological
changes in a skin biopsy after von Kossa staining; and the presence of
peau d'orange, angioid streaks, or comet-like streaks in the retina. The
mother of this family and one of her sons fulfilled all 3 criteria.
Plomp et al. (2004) stated that the R1459C mutation might be one that
could cause PXE in the heterozygous state (177850). In their review of
families with putative autosomal dominant PXE, including this family and
2 others examined by them, the authors noted that they did not find a
single family with definite PXE in 3 or more generations.

Bergen (2006) stated that the family with the apparently heterozygous
R1459C mutation studied by Plomp et al. (2004) remained 'an interesting
puzzle and is perhaps the always existing 'exception to the rule'.'

.0019
PSEUDOXANTHOMA ELASTICUM
ABCC6, VAL1298PHE

In a cohort of 122 unrelated patients with PXE (264800) from several
countries, Le Saux et al. (2001) found a 3892G-T transversion in exon 28
of the ABCC6 gene that resulted in a val1298-to-phe (V1298F)
substitution. The mutation was present in heterozygosity in 2 alleles
from patients from the United States, for an allele frequency among 74
United States alleles of 2.7%. The mutation was not found in the
European population.

Ilias et al. (2002) showed that the V1298F mutation, localized to the
C-terminal cytoplasmic domain of ABCC6, did not affect the expression of
the ABCC6 protein in infected insect cells, but that the protein was
essentially inactive in the MgATP-dependent transport of
N-ethylmaleimide S-glutathione (NEM-GS) or leukotriene-C4.

.0020
PSEUDOXANTHOMA ELASTICUM
ABCC6, GLY1302ARG

In a cohort of 122 unrelated patients with PXE (264800) from several
countries, Le Saux et al. (2001) found a 3904G-A transition in exon 28
of the ABCC6 gene that resulted in a gly1302-to-arg (G1302R) amino acid
substitution in the second intracellular nucleotide-binding domain. The
mutation, present in homozygosity, occurred in a total of 4 alleles from
patients from the United States, giving an allele frequency of 5.4% in a
total of 74 United States alleles. It was not found in the European
population.

Ilias et al. (2002) showed that the G1302R mutation did not affect the
expression of the ABCC6 protein in infected insect cells, but that the
protein was essentially inactive in the MgATP-dependent transport of
N-ethylmaleimide S-glutathione (NEM-GS) or leukotriene-C4.

.0021
PSEUDOXANTHOMA ELASTICUM
ABCC6, GLY1321SER

In a cohort of 122 unrelated patients with PXE (264800) from several
countries, Le Saux et al. (2001) found a 3961G-A transition in exon 28
of the ABCC6 gene that resulted in a gly1321-to-ser (G1321S)
substitution in the second intracellular nucleotide-binding domain. They
found the mutation in heterozygosity in 1 of 74 United States alleles,
for an allele frequency of 1.4%. It was not found in the European
population.

Ilias et al. (2002) showed that the G1321S mutation did not affect the
expression of the ABCC6 protein in infected insect cells, but that the
protein was essentially inactive in the MgATP-dependent transport of
N-ethylmaleimide S-glutathione (NEM-GS) or leukotriene-C4.

.0022
PSEUDOXANTHOMA ELASTICUM
ABCC6, ASP1238HIS

Chassaing et al. (2004) described a pedigree of PXE (264800) with
pseudodominant inheritance. Two affected sibs carried 3 distinct
mutations of the ABCC6 gene. The brother carried a 3712G-C transversion
in exon 26 that resulted in an asp1238-to-his substitution (D1238H), and
a 3389C-T transition in exon 24 that resulted in a thr1130-to-met
substitution (T1130M; 603234.0024). His sister carried the T1130M
mutation and a 33-bp deletion (603234.0023). The mother, who had PXE
also, was deduced to a compound heterozygote for the deletion and
T1130M, whereas the father was assumed to be heterozygous for the D1238H
mutation which was shared by the sibs; however, DNA was not available
for study on either parent.

.0023
PSEUDOXANTHOMA ELASTICUM
ABCC6, 33-BP DEL

In the Algerian pedigree studied by Chassaing et al. (2004), a female
patient with PXE (264800) carried a 33-bp deletion in exon 9 of the
ABCC6 gene (1088-1120del) in compound heterozygosity with a missense
mutation (603234.0024). The mutation led to the deletion of 11 amino
acids in the transmembrane and intracellular domains (Q363_R373del).

.0024
PSEUDOXANTHOMA ELASTICUM
ABCC6, THR1130MET

See 603234.0022 and Chassaing et al. (2004). The T1130M substitution
arose from a 3389C-T transition in exon 24.

.0025
PSEUDOXANTHOMA ELASTICUM
ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2, INCLUDED
ABCC6, ARG765GLN

In a 28-year-old French man with pseudoxanthoma elasticum (PXE; 264800),
who had a younger brother who died of generalized arterial calcification
of infancy (GACI2; 614473) at age 15 months, Le Boulanger et al. (2010)
identified compound heterozygosity for missense mutations in the ABCC6
gene, an arg765-to-gln (R765Q) substitution and a gln1406-to-lys
(Q1406K; 603234.0026) substitution. The mutations were found in
heterozygosity in each of his unaffected parents, respectively. Although
no DNA material was available from the deceased younger brother, his
disease was presumed to be related to the familial ABCC6 mutations. Le
Boulanger et al. (2010) concluded that GACI may represent an atypical
and severe end of the vascular phenotype spectrum of PXE. (The mutations
identified by Le Boulanger et al. (2010) were listed as R765Q and Q1406K
in their text, but as E765Q and E1406K in their Figure 3.)

The R765Q mutation in exon 18 of the ABCC6 gene has also been identified
in heterozygosity and in compound heterozygosity with another ABCC6
mutation in patients with PXE (see Le Saux et al., 2001 and Miksch et
al., 2005, respectively).

.0026
PSEUDOXANTHOMA ELASTICUM
ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2, INCLUDED
ABCC6, GLN1406LYS

See 603234.0025 and Le Boulanger et al. (2010).

.0027
ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2
PSEUDOXANTHOMA ELASTICUM, INCLUDED
ABCC6, ARG518TER

In a 3-year-old Spanish boy with generalized arterial calcification of
infancy (GACI2; 614473), who had calcification of the splenic and
pancreatic arteries, nephrocalcinosis, severe hypertension,
cardiomegaly, psychomotor retardation, and abdominal distention,
Nitschke et al. (2012) identified compound heterozygosity for 2
mutations in the ABCC6 gene: an R1141X substitution (603234.0001) and a
1552C-T transition in exon 12, resulting in an arg518-to-ter (R518X)
substitution.

The R518X mutation has also been identified in compound heterozygosity
with another ABCC6 mutation in patients with pseudoxanthoma elasticum
(PXE; 264800) (see, e.g., Meloni et al., 2001 and Miksch et al., 2005).

.0028
ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2
ABCC6, 1-BP INS, 450C

See 603234.0006 and Nitschke et al. (2012).

.0029
ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2
PSEUDOXANTHOMA ELASTICUM, INCLUDED
ABCC6, IVS21, G-T, +1

In a Canadian female infant with generalized arterial calcification of
infancy (GACI2; 614473), originally reported by Glatz et al. (2006), who
died at 6.5 weeks of age of myocardial infarction with calcification of
the aorta and coronary, pulmonary, and renal arteries and occlusion of
the right coronary artery, Nitschke et al. (2012) identified compound
heterozygosity for 2 splice site mutations in the ABCC6 gene, a G-T
transversion in intron 21 (IVS21+1G-T) and a IVS26-1G-A (603234.0015),
both predicted to cause a frameshift resulting in a premature
termination codon. The latter mutation had previously been identified in
compound heterozygosity in a patient with pseudoxanthoma elasticum (PXE;
264800).

The IVS21+1G-T splice-site mutation has also been identified in compound
heterozygosity with another ABCC6 mutation in PXE patients (see, e.g.,
Le Saux et al., 2001 and Miksch et al., 2005).

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45. Ratajewski, M.; Bartosz, G.; Pulaski, L.: Expression of the human
ABCC6 gene is induced by retinoids through the retinoid X receptor. Biochem.
Biophys. Res. Commun. 350: 1082-1087, 2006.

46. Ratajewski, M.; Van de Ven, W. J. M.; Bartosz, G.; Pulaski, L.
: The human pseudoxanthoma elasticum gene ABCC6 is transcriptionally
regulated by PLAG family transcription factors. Hum. Genet. 124:
451-463, 2008.

47. Ringpfeil, F.; Lebwohl, M.G.; Christiano, A. M.; Uitto, J.: Pseudoxanthoma
elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding
cassette (ABC) transporter. Proc. Nat. Acad. Sci. 97: 6001-6006,
2000.

48. Ringpfeil, F.; Nakano, A.; Uitto, J.; Pulkkinen, L.: Compound
heterozygosity for a recurrent 16.5-kb Alu-mediated deletion mutation
and single-base-pair substitutions in the ABCC6 gene results in pseudoxanthoma
elasticum. Am. J. Hum. Genet. 68: 642-652, 2001.

49. Ringpfeil, F.; Pulkkinen, L.; Uitto, J.: Molecular genetics of
pseudoxanthoma elasticum. Exp. Derm. 10: 221-228, 2001.

50. Sherer, D. W.; Bercovitch, L.; Lebwohl, M.: Pseudoxanthoma elasticum:
significance of limited phenotypic expression in parents of affected
offspring. J. Am. Acad. Derm. 44: 534-537, 2001.

51. Sinko, E.; Ilias, A.; Ujhelly, O.; Homolya, L.; Scheffer, G. L.;
Bergen, A. A. B.; Sarkadi, B.; Varadi, A.: Subcellular localization
and N-glycosylation of human ABCC6, expressed in MDCKII cells. Biochem.
Biophys. Res. Commun. 308: 263-269, 2003.

52. Torrington, M.; Viljoen, D. L.: Founder effect in 20 Afrikaner
kindreds with pseudoxanthoma elasticum. S. Afr. Med. J. 79: 7-11,
1991.

53. Trip, M. D.; Smulders, Y. M.; Wegman, J. J.; Hu, X.; Boer, J.
M.; ten Brink, J. B.; Zwinderman, A. H.; Kastelein, J. J.; Feskens,
E. J.; Bergen, A. A.: Frequent mutation in the ABCC6 gene (R1141X)
is associated with a strong increase in the prevalence of coronary
artery disease. Circulation 106: 773-775, 2002.

54. van Soest, S.; Swart, J.; Tijmes, N.; Sandkuijl, L. A.; Rommers,
J.; Bergen, A. A. B.: A locus for autosomal recessive pseudoxanthoma
elasticum, with penetrance of vascular symptoms in carriers, maps
to chromosome 16p13.1. Genome Res. 7: 830-834, 1997.

*FIELD* CN
Marla J. F. O'Neill - updated: 2/8/2012
Ada Hamosh - updated: 6/18/2010
Cassandra L. Kniffin - updated: 3/25/2010
Cassandra L. Kniffin - updated: 10/14/2009
Patricia A. Hartz - updated: 1/6/2009
George E. Tiller - updated: 10/28/2008
Patricia A. Hartz - updated: 8/5/2008
Victor A. McKusick - updated: 12/28/2007
Marla J. F. O'Neill - updated: 4/30/2007
Victor A. McKusick - updated: 3/6/2007
Patricia A. Hartz - updated: 2/28/2007
Matthew B. Gross - updated: 11/29/2006
Victor A. McKusick - edited: 9/21/2005
Cassandra L. Kniffin - updated: 4/1/2004
Jane Kelly - updated: 8/22/2003
Victor A. McKusick - updated: 3/10/2003
Victor A. McKusick - updated: 11/13/2002
Victor A. McKusick - updated: 10/17/2001
Victor A. McKusick - updated: 3/19/2001
Victor A. McKusick - updated: 5/30/2000
Ada Hamosh - updated: 5/22/2000
Jennifer P. Macke - updated: 12/2/1998

*FIELD* CD
Jennifer P. Macke: 10/29/1998

*FIELD* ED
carol: 10/01/2013
alopez: 7/18/2012
carol: 2/8/2012
terry: 2/8/2012
carol: 2/8/2012
alopez: 6/29/2010
terry: 6/18/2010
wwang: 6/18/2010
ckniffin: 3/25/2010
ckniffin: 11/3/2009
wwang: 10/30/2009
ckniffin: 10/14/2009
alopez: 5/13/2009
mgross: 1/8/2009
terry: 1/6/2009
wwang: 10/28/2008
wwang: 8/5/2008
alopez: 1/24/2008
terry: 12/28/2007
wwang: 10/3/2007
wwang: 4/30/2007
alopez: 3/13/2007
alopez: 3/9/2007
terry: 3/6/2007
alopez: 2/28/2007
mgross: 11/29/2006
joanna: 12/20/2005
alopez: 10/12/2005
alopez: 9/21/2005
carol: 4/9/2004
ckniffin: 4/1/2004
ckniffin: 10/17/2003
carol: 8/22/2003
carol: 3/18/2003
tkritzer: 3/13/2003
terry: 3/10/2003
tkritzer: 11/22/2002
tkritzer: 11/15/2002
terry: 11/13/2002
carol: 8/9/2002
carol: 7/31/2002
carol: 1/3/2002
carol: 11/21/2001
mcapotos: 10/30/2001
mcapotos: 10/25/2001
terry: 10/17/2001
cwells: 3/29/2001
terry: 3/19/2001
mcapotos: 9/5/2000
carol: 6/14/2000
carol: 6/1/2000
carol: 5/30/2000
alopez: 5/22/2000
carol: 11/9/1999
alopez: 12/2/1998
alopez: 10/29/1998

MIM 614473
*RECORD*
*FIELD* NO
614473
*FIELD* TI
#614473 ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2; GACI2
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moregeneralized arterial calcification of infancy-2 (GACI2) can be caused by
homozygous or compound heterozygous mutation in the ABCC6 gene (603234)
on chromosome 16p13.11.

DESCRIPTION

Generalized arterial calcification of infancy (GACI) is a severe
autosomal recessive disorder characterized by calcification of the
internal elastic lamina of muscular arteries and stenosis due to
myointimal proliferation. GACI is often fatal within the first 6 months
of life because of myocardial ischemia resulting in refractory heart
failure (summary by Rutsch et al., 2003 and Cheng et al., 2005).

For a general phenotypic description and a discussion of genetic
heterogeneity of GACI, see GACI1 (208000).

Pseudoxanthoma elasticum (PXE; 264800) is an allelic disorder caused by
mutation in the ABCC6 gene; it has been suggested that GACI and PXE
represent 2 ends of a clinical spectrum of ectopic calcification and
other organ pathologies rather than 2 distinct disorders (Nitschke et
al., 2012).

CLINICAL FEATURES

Glatz et al. (2006) described 2 patients with idiopathic infantile
arterial calcification (IIAC). The first was an infant girl who
presented at 33 days of life with tachypnea, tachycardia, cool
extremities, and poor peripheral pulses. Echocardiography demonstrated
cardiac dysfunction and an electrocardiogram and cardiac enzyme levels
were suggestive of myocardial infarction (MI). Despite intensive care,
her condition deteriorated over the next 2 weeks and the patient died
after withdrawal of support at 6.5 weeks of age. Autopsy revealed a
markedly enlarged heart, with multiple areas of focal hemorrhage,
necrosis, and calcification consistent with MI. Microscopic examination
of the vasculature revealed calcification of all major coronary
arteries, as well as involvement of the aorta, main and branch pulmonary
arteries, celiac, hepatic, suprarenal, pancreaticoduodenal, splenic,
mesenteric, renal, and lumbar arteries. Involved arteries showed
calcification primarily of the internal elastic lamina, with varying
degrees of calcification of the external elastic lamina in areas of
heavy calcification, which was circumferential in many sections.
Inflammation was not a prominent feature. Intraparenchymal arterial
calcifications were found in the spleen, pancreas, diaphragm, thymus,
thyroid, trachea, larynx, and salivary glands. Extensive intratubular
calcifications were found in the kidneys. Gross examination of the brain
showed mild convolutional abnormalities, and microscopy showed rare
focal parenchymal calcifications and a single vessel in the corpus
striatum with early calcific changes. The second patient with IIAC was
an infant girl who presented at age 2 months in cardiogenic shock, and
after initial recovery was readmitted in the third month of life with
severe heart failure, at which time cardiac MRI showed a large
anterolateral and apical aneurysm of the left ventricle, with thinning
of the myocardium and moderate to severe mitral regurgitation. The
patient had progressively intractable heart failure and died at 4.5
months of age. Autopsy revealed a severely enlarged heart, with severe
ischemic changes in the myocardium of the left ventricle and
calcification within the subendocardial area. Upon microscopic
examination of the arterial system, elastic arteries showed
calcification primarily of the outer elastic layers, whereas muscular
arteries had preferential calcification of the media with intimal
proliferation, accompanied by a foreign body giant cell reaction. These
findings were present in the coronary, pulmonary, and renal arteries, as
well as the aorta and its branches in the neck. The coronary arteries
showed luminal obstruction with near-occlusive changes in segments.
Examined veins were normal.

- Intrafamilial Phenotypic Variability

Le Boulanger et al. (2010) studied a nonconsanguineous French family in
which a younger brother died of a condition 'strikingly reminiscent' of
generalized arterial calcification of infancy (GACI) at 15 months of
age, whereas his older brother developed uncomplicated pseudoxanthoma
elasticum (PXE; 264800) in adolescence. The younger brother had a
myocardial infarction complicated by heart failure at 6 months of age;
skin biopsy at 1 year of age for evaluation of a possible connective
tissue disorder showed elastic fiber dystrophy, with clumped and
fragmented fibers in the mid dermis, as well as calcifications on the
elastic fibers and sporadically in vessel walls of the subcutis. There
were no periarticular calcifications on x-ray, and serum phosphate and
calcium levels were normal. At 15 months of age, he had a second, fatal
MI. Autopsy showed fibrosis of the coronary arteries with calcifications
involving the intima, internal elastic lamina, and media, and
medium-sized arteries in the adrenal glands, pancreas, thyroid, and
testes also showed extensive arterial calcification. At 28 years of age,
the older brother presented for evaluation of yellowish papules on his
neck; he had no cardiovascular symptoms and cardiac examination and
echocardiography were normal. Skin samples from the brother with PXE
showed heavy staining of mineralized mid-dermal elastic fibers, with
active MGP (154870) and fetuin-A (AHSG; 138680) antibodies, and fetuin-A
also showed striking staining of the subepidermal area. All arteries in
autopsy samples from the brother with GACI showed the same
immunohistochemical profile, as well as calcifications.

MOLECULAR GENETICS

In an infant girl with generalized arterial calcification who died at
6.5 weeks of age, Glatz et al. (2006) analyzed the gene associated with
GACI1 (208000), ENPP1 (173335), but no pathogenic mutations were found.
Nitschke et al. (2012) restudied this patient and identified compound
heterozygosity for splice site mutations in the ABCC6 gene (603234.0015
and 603234.0029).

In a 28-year-old French man with pseudoxanthoma elasticum (PXE; 264800),
who had a younger brother who died of GACI at age 15 months, Le
Boulanger et al. (2010) identified compound heterozygosity for missense
mutations in the known causative gene for PXE, ABCC6 (603234.0025 and
603234.0026), which were also found in heterozygosity in each of his
unaffected parents, respectively. No disease-causing mutations were
found in ENPP1. Although no DNA material was available from the deceased
younger brother, his disease was presumed to be related to the familial
ABCC6 mutations. Le Boulanger et al. (2010) concluded that GACI may
represent an atypical and severe end of the vascular phenotypic spectrum
of PXE.

Nitschke et al. (2012) analyzed the ABCC6 gene in 28 GACI patients from
25 unrelated families who were negative for mutation in the ENNP1 gene,
as well as 2 unrelated GACI patients in whom only 1 ENNP1 mutation had
been detected. They identified homozygosity or compound heterozygosity
for mutations in ABCC6 in 8 unrelated GACI patients (see, e.g.,
603234.0001 and 603234.0006, and 603234.0027-603234.0029), including 1
of the infant girls originally described by Glatz et al. (2006) (see
603234.0029). In 6 patients from 5 unrelated families, only 1 mutation
was detected in ABCC6; the authors noted that there was no phenotypic
difference between these patients and those with biallelic mutations in
ABCC6, and stated that mutations in regulatory untranslated regions of
ABCC6 might not have been detected by their approach. No mutation in the
ABCC6 gene was found in 16 patients from 14 unrelated families,
including the 2 patients who were known to carry monoallelic mutations
in ENNP1. Overall, 13 different ABCC6 mutations were identified in GACI
patients, all but 2 of which had previously been identified in typical
PXE patients who had a much milder phenotype than the GACI patients.
Based on the considerable overlap of phenotype and genotype of GACI and
pseudoxanthoma elasticum, Nitschke et al. (2012) suggested that GACI and
PXE represent 2 ends of a clinical spectrum of ectopic calcification and
other organ pathologies, rather than 2 distinct disorders.

*FIELD* RF
1. Cheng, K.-S.; Chen, M.-R.; Ruf, N.; Lin, S.-P.; Rutsch, F.: Generalized
arterial calcification of infancy: different clinical courses in two
affected siblings. Am. J. Med. Genet. 136A: 210-213, 2005.

2. Glatz, A. C.; Pawel, B. R.; Hsu, D. T.; Weinberg, P.; Chrisant,
M. R. K.: Idiopathic infantile arterial calcification: two case reports,
a review of the literature and a role for cardiac transplantation. Pediat.
Transplant. 10: 225-233, 2006.

3. Le Boulanger, G.; Labreze, C.; Croue, A.; Schurgers, L. J.; Chassaing,
N.; Wittkampf, T.; Rutsch, F.; Martin, L.: An unusual severe vascular
case of pseudoxanthoma elasticum presenting as generalized arterial
calcification of infancy. Am. J. Med. Genet. 152A: 118-123, 2010.

4. Nitschke, Y.; Baujat, G.; Botschen, U.; Wittkampf, T.; du Moulin,
M.; Stella, J.; Le Merrer, M.; Guest, G.; Lambot, K.; Tazarourte-Pinturier,
M.-F.; Chassaing, N.; Roche, O.; and 19 others: Generalized arterial
calcification of infancy and pseudoxanthoma elasticum can be caused
by mutations in either ENPP1 or ABCC6. Am. J. Hum. Genet. 90: 25-39,
2012.

5. Rutsch, F.; Rui, N.; Vaingankar, S.; Toliat, M. R.; Suk, A.; Hohne,
W.; Schauer, G.; Lehmann, M.; Roscioli, T.; Schnabel, D.; Epplen,
J. T.; Knisely, A.; and 10 others: Mutations in ENPP1 are associated
with 'idiopathic' infantile arterial calcification. Nature Genet. 34:
379-381, 2003.

*FIELD* CS
INHERITANCE:
Autosomal recessive

CARDIOVASCULAR:
[Heart];
Coronary artery calcification;
Cardiac dysfunction;
Myocardial infarction (in some patients);
Heart failure;
[Vascular];
Generalized calcification of arteries, including aorta and intraparenchymal
arteries;
Hypertension (in some patients)

GENITOURINARY:
[Kidneys];
Calcification of renal arteries;
Nephrocalcinosis (in some patients);
Tubular calcification (in some patients)

SKELETAL:
[Limbs];
Hypophosphatemic rickets (in some patients)

METABOLIC FEATURES:
Hypophosphatemic rickets (in some patients)

MISCELLANEOUS:
Most patients die in infancy Features of pseudoxanthoma elasticum,
an allelic disorder, have not yet been reported in GACI2 patients
(the 4 surviving patients reported as of January 2012 are all age
5 years or less)

MOLECULAR BASIS:
Caused by mutation in the ATP-binding cassette, subfamily C, member
6 gene (ABCC6, 603234.0001)

*FIELD* CD
Marla J. F. O'Neill: 2/10/2012

*FIELD* ED
joanna: 02/10/2012

*FIELD* CD
Marla J. F. O'Neill: 2/8/2012

*FIELD* ED
joanna: 05/22/2012
terry: 2/15/2012
carol: 2/8/2012

RBCC Red Blood Cell Collection

Full text data of ABCC6