RBCC

Full text data of TGFB1

TGFB1 (TGFB) [Confidence: low (only semi-automatic identification from reviews)]
Transforming growth factor beta-1; TGF-beta-1; Latency-associated peptide; LAP; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P01137
ID TGFB1_HUMAN Reviewed; 390 AA.
AC P01137; A8K792; Q9UCG4;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1991, sequence version 2.
DT 22-JAN-2014, entry version 190.
DE RecName: Full=Transforming growth factor beta-1;
DE Short=TGF-beta-1;
DE Contains:
DE RecName: Full=Latency-associated peptide;
DE Short=LAP;
DE Flags: Precursor;
GN Name=TGFB1; Synonyms=TGFB;
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 [GENOMIC DNA].
RX PubMed=3470709; DOI=10.1093/nar/15.7.3188;
RA Derynck R., Rhee L., Chen E.Y., van Tilburg A.;
RT "Intron-exon structure of the human transforming growth factor-beta
RT precursor gene.";
RL Nucleic Acids Res. 15:3188-3189(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS PRO-10 AND PRO-25.
RX PubMed=3861940; DOI=10.1038/316701a0;
RA Derynck R., Jarrett J.A., Chen E.Y., Eaton D.H., Bell J.R.,
RA Assoian R.K., Roberts A.B., Sporn M.B., Goeddel D.V.;
RT "Human transforming growth factor-beta complementary DNA sequence and
RT expression in normal and transformed cells.";
RL Nature 316:701-705(1985).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Duodenum, and Eye;
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 NUCLEOTIDE SEQUENCE [MRNA] OF 279-390.
RC TISSUE=Carcinoma;
RA Urushizaki Y., Niitsu Y., Terui T., Koshida Y., Mahara K., Kohgo Y.,
RA Urushizaki I., Takahashi Y., Ito H.;
RT "Cloning and expression of the gene for human transforming growth
RT factor-beta in Escherichia coli.";
RL Tumor Res. 22:41-55(1987).
RN [8]
RP PROTEIN SEQUENCE OF 279-329.
RC TISSUE=Urinary bladder carcinoma;
RX PubMed=8471846; DOI=10.1006/prep.1993.1019;
RA Bourdrel L., Lin C.-H., Lauren S.L., Elmore R.H., Sugarman B.J.,
RA Hu S., Westcott K.R.;
RT "Recombinant human transforming growth factor-beta 1: expression by
RT Chinese hamster ovary cells, isolation, and characterization.";
RL Protein Expr. Purif. 4:130-140(1993).
RN [9]
RP PROTEIN SEQUENCE OF 279-301.
RX PubMed=2982829;
RA Massague J., Like B.;
RT "Cellular receptors for type beta transforming growth factor. Ligand
RT binding and affinity labeling in human and rodent cell lines.";
RL J. Biol. Chem. 260:2636-2645(1985).
RN [10]
RP PROTEIN SEQUENCE OF 30-42 AND 279-290, AND CHARACTERIZATION.
RX PubMed=3162913;
RA Miyazono K., Hellman U., Wernstedt C., Heldin C.H.;
RT "Latent high molecular weight complex of transforming growth factor
RT beta 1. Purification from human platelets and structural
RT characterization.";
RL J. Biol. Chem. 263:6407-6415(1988).
RN [11]
RP REVIEW.
RX PubMed=9150447; DOI=10.1038/ki.1997.188;
RA Munger J.S., Harpel J.G., Gleizes P.E., Mazzieri R., Nunes I.,
RA Rifkin D.B.;
RT "Latent transforming growth factor-beta: structural features and
RT mechanisms of activation.";
RL Kidney Int. 51:1376-1382(1997).
RN [12]
RP INTERACTION WITH DPT.
RX PubMed=9895299; DOI=10.1042/0264-6021:3370537;
RA Okamoto O., Fujiwara S., Abe M., Sato Y.;
RT "Dermatopontin interacts with transforming growth factor beta and
RT enhances its biological activity.";
RL Biochem. J. 337:537-541(1999).
RN [13]
RP TISSUE SPECIFICITY.
RX PubMed=11746498; DOI=10.1002/jcb.1249;
RA Shur I., Lokiec F., Bleiberg I., Benayahu D.;
RT "Differential gene expression of cultured human osteoblasts.";
RL J. Cell. Biochem. 83:547-553(2001).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-82, AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [15]
RP INTERACTION WITH CD109.
RX PubMed=16754747; DOI=10.1096/fj.05-5229fje;
RA Finnson K.W., Tam B.Y.Y., Liu K., Marcoux A., Lepage P., Roy S.,
RA Bizet A.A., Philip A.;
RT "Identification of CD109 as part of the TGF-beta receptor system in
RT human keratinocytes.";
RL FASEB J. 20:1525-1527(2006).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-82, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.M500324-MCP200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [17]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INTERACTION WITH ASPN.
RX PubMed=17827158; DOI=10.1074/jbc.M700522200;
RA Nakajima M., Kizawa H., Saitoh M., Kou I., Miyazono K., Ikegawa S.;
RT "Mechanisms for asporin function and regulation in articular
RT cartilage.";
RL J. Biol. Chem. 282:32185-32192(2007).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [19]
RP STRUCTURE BY NMR OF 279-390.
RX PubMed=8424942; DOI=10.1021/bi00055a021;
RA Archer S.J., Bax A., Roberts A.B., Sporn M.B., Ogawa Y., Piez K.A.,
RA Weatherbee J.A., Tsang M.L.-S., Lucas R., Zheng B.-L., Wenker J.,
RA Torchia D.A.;
RT "Transforming growth factor beta 1: NMR signal assignments of the
RT recombinant protein expressed and isotopically enriched using Chinese
RT hamster ovary cells.";
RL Biochemistry 32:1152-1163(1993).
RN [20]
RP STRUCTURE BY NMR OF 279-390.
RX PubMed=8424943; DOI=10.1021/bi00055a022;
RA Archer S.J., Bax A., Roberts A.B., Sporn M.B., Ogawa Y., Piez K.A.,
RA Weatherbee J.A., Tsang M.L.-S., Lucas R., Zheng B.-L., Wenker J.,
RA Torchia D.A.;
RT "Transforming growth factor beta 1: secondary structure as determined
RT by heteronuclear magnetic resonance spectroscopy.";
RL Biochemistry 32:1164-1171(1993).
RN [21]
RP STRUCTURE BY NMR OF 279-390.
RX PubMed=8679613; DOI=10.1021/bi9604946;
RA Hinck A.P., Archer S.J., Qian S.W., Roberts A.B., Sporn M.B.,
RA Weatherbee J.A., Tsang M.L.-S., Lucas R., Zheng B.-L., Wenker J.,
RA Torchia D.A.;
RT "Transforming growth factor beta 1: three-dimensional structure in
RT solution and comparison with the X-ray structure of transforming
RT growth factor beta 2.";
RL Biochemistry 35:8517-8534(1996).
RN [22]
RP VARIANT PRO-10.
RX PubMed=9783545; DOI=10.1359/jbmr.1998.13.10.1569;
RA Yamada Y., Miyauchi A., Goto J., Takagi Y., Okuizumi H., Kanematsu M.,
RA Hase M., Takai H., Harada A., Ikeda K.;
RT "Association of a polymorphism of the transforming growth factor-beta1
RT gene with genetic susceptibility to osteoporosis in postmenopausal
RT Japanese women.";
RL J. Bone Miner. Res. 13:1569-1576(1998).
RN [23]
RP VARIANTS CE CYS-218; HIS-218 AND ARG-225.
RX PubMed=10973241; DOI=10.1038/79128;
RA Kinoshita A., Saito T., Tomita H., Makita Y., Yoshida K., Ghadami M.,
RA Yamada K., Kondo S., Ikegawa S., Nishimura G., Fukushima Y.,
RA Nakagomi T., Saito H., Sugimoto T., Kamegaya M., Hisa K., Murray J.C.,
RA Taniguchi N., Niikawa N., Yoshiura K.;
RT "Domain-specific mutations in TGFB1 result in Camurati-Engelmann
RT disease.";
RL Nat. Genet. 26:19-20(2000).
RN [24]
RP VARIANTS CE HIS-81; CYS-218 AND ARG-225.
RX PubMed=11062463; DOI=10.1038/81563;
RA Janssens K., Gershoni-Baruch R., Guanabens N., Migone N., Ralston S.,
RA Bonduelle M., Lissens W., Van Maldergem L., Vanhoenacker F.,
RA Verbruggen L., Van Hul W.;
RT "Mutations in the gene encoding the latency-associated peptide of TGF-
RT beta 1 cause Camurati-Engelmann disease.";
RL Nat. Genet. 26:273-275(2000).
RN [25]
RP VARIANT PRO-10.
RX PubMed=12202987; DOI=10.1007/s100380200069;
RA Watanabe Y., Kinoshita A., Yamada T., Ohta T., Kishino T.,
RA Matsumoto N., Ishikawa M., Niikawa N., Yoshiura K.;
RT "A catalog of 106 single-nucleotide polymorphisms (SNPs) and 11 other
RT types of variations in genes for transforming growth factor-beta1
RT (TGF-beta1) and its signaling pathway.";
RL J. Hum. Genet. 47:478-483(2002).
RN [26]
RP CHARACTERIZATION OF VARIANTS CE HIS-81; CYS-218; ASP-222 AND ARG-225.
RX PubMed=12493741; DOI=10.1074/jbc.M208857200;
RA Janssens K., ten Dijke P., Ralston S.H., Bergmann C., Van Hul W.;
RT "Transforming growth factor-beta-1 mutations in Camurati-Engelmann
RT disease lead to increased signaling by altering either activation or
RT secretion of the mutant protein.";
RL J. Biol. Chem. 278:7718-7724(2003).
RN [27]
RP CHARACTERIZATION OF VARIANT CE CYS-218.
RX PubMed=12843182; DOI=10.1210/jc.2002-020564;
RA McGowan N.W., MacPherson H., Janssens K., Van Hul W., Frith J.C.,
RA Fraser W.D., Ralston S.H., Helfrich M.H.;
RT "A mutation affecting the latency-associated peptide of TGFbeta1 in
RT Camurati-Engelmann disease enhances osteoclast formation in vitro.";
RL J. Clin. Endocrinol. Metab. 88:3321-3326(2003).
RN [28]
RP VARIANTS CE GLY-223 AND ARG-223.
RX PubMed=15103729; DOI=10.1002/ajmg.a.20671;
RA Kinoshita A., Fukumaki Y., Shirahama S., Miyahara A., Nishimura G.,
RA Haga N., Namba A., Ueda H., Hayashi H., Ikegawa S., Seidel J.,
RA Niikawa N., Yoshiura K.;
RT "TGFB1 mutations in four new families with Camurati-Engelmann disease:
RT confirmation of independently arising LAP-domain-specific mutations.";
RL Am. J. Med. Genet. 127A:104-107(2004).
CC -!- FUNCTION: Multifunctional protein that controls proliferation,
CC differentiation and other functions in many cell types. Many cells
CC synthesize TGFB1 and have specific receptors for it. It positively
CC and negatively regulates many other growth factors. It plays an
CC important role in bone remodeling as it is a potent stimulator of
CC osteoblastic bone formation, causing chemotaxis, proliferation and
CC differentiation in committed osteoblasts.
CC -!- SUBUNIT: Homodimer; disulfide-linked, or heterodimer with TGFB2
CC (By similarity). Secreted and stored as a biologically inactive
CC form in the extracellular matrix in a 290 kDa complex (large
CC latent TGF-beta1 complex) containing the TGFB1 homodimer, the
CC latency-associated peptide (LAP), and the latent TGFB1 binding
CC protein-1 (LTBP1). The complex without LTBP1 is known as the'small
CC latent TGF-beta1 complex'. Dissociation of the TGFB1 from LAP is
CC required for growth factor activation and biological activity.
CC Release of the large latent TGF-beta1 complex from the
CC extracellular matrix is carried out by the matrix
CC metalloproteinase MMP3 (By similarity). May interact with THSD4;
CC this interaction may lead to sequestration by FBN1 microfibril
CC assembly and attenuation of TGFB signaling. Interacts with the
CC serine proteases, HTRA1 and HTRA3: the interaction with either
CC inhibits TGFB1-mediated signaling. The HTRA protease activity is
CC required for this inhibition (By similarity). Latency-associated
CC peptide interacts with NREP; the interaction results in a decrease
CC in TGFB1 autoinduction (By similarity). Interacts with CD109, DPT
CC and ASPN.
CC -!- INTERACTION:
CC P05067:APP; NbExp=2; IntAct=EBI-779636, EBI-77613;
CC Q14689:DIP2A; NbExp=2; IntAct=EBI-779636, EBI-2564275;
CC P17813:ENG; NbExp=2; IntAct=EBI-779636, EBI-2834630;
CC Q12841:FSTL1; NbExp=2; IntAct=EBI-779636, EBI-2349801;
CC P36897:TGFBR1; NbExp=2; IntAct=EBI-779636, EBI-1027557;
CC P37173:TGFBR2; NbExp=6; IntAct=EBI-779636, EBI-296151;
CC Q03167:TGFBR3; NbExp=2; IntAct=EBI-779636, EBI-2852679;
CC Q90998:TGFBR3 (xeno); NbExp=2; IntAct=EBI-779636, EBI-6620843;
CC P07996:THBS1; NbExp=2; IntAct=EBI-779636, EBI-2530274;
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular
CC matrix.
CC -!- TISSUE SPECIFICITY: Highly expressed in bone. Abundantly expressed
CC in articular cartilage and chondrocytes and is increased in
CC osteoarthritis (OA). Colocalizes with ASPN in chondrocytes within
CC OA lesions of articular cartilage.
CC -!- INDUCTION: Activated in vitro at pH below 3.5 and over 12.5.
CC -!- DOMAIN: The 'straitjacket' and 'arm' domains encircle the growth
CC factor monomers and are fastened together by strong bonding
CC between Lys-56 and Tyr-103/Tyr-104. Activation of TGF-beta1
CC requires the binding of integrin alpha-V to an RGD sequence in the
CC prodomain and exertion of force on this domain, which is held in
CC the extracellular matrix by latent TGF-beta binding proteins. The
CC sheer physical force unfastens the straitjacket and releases the
CC active growth factor dimer (By similarity).
CC -!- PTM: Glycosylated.
CC -!- PTM: The precursor is cleaved into mature TGF-beta-1 and LAP,
CC which remains non-covalently linked to mature TGF-beta-1 rendering
CC it inactive.
CC -!- POLYMORPHISM: In post-menopausal Japanese women, the frequency of
CC Leu-10 is higher in subjects with osteoporosis than in controls.
CC -!- DISEASE: Camurati-Engelmann disease (CE) [MIM:131300]: Autosomal
CC dominant disorder characterized by hyperostosis and sclerosis of
CC the diaphyses of long bones. The disease typically presents in
CC early childhood with pain, muscular weakness and waddling gait,
CC and in some cases other features such as exophthalmos, facial
CC paralysis, hearing difficulties and loss of vision. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the TGF-beta family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/TGFB1";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=TGF beta-1 entry;
CC URL="http://en.wikipedia.org/wiki/TGF_beta_1";
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DR EMBL; X05839; CAA29283.1; -; Genomic_DNA.
DR EMBL; X05840; CAA29283.1; JOINED; Genomic_DNA.
DR EMBL; X05843; CAA29283.1; JOINED; Genomic_DNA.
DR EMBL; X05844; CAA29283.1; JOINED; Genomic_DNA.
DR EMBL; X05849; CAA29283.1; JOINED; Genomic_DNA.
DR EMBL; X05850; CAA29283.1; JOINED; Genomic_DNA.
DR EMBL; X02812; CAA26580.1; -; mRNA.
DR EMBL; BT007245; AAP35909.1; -; mRNA.
DR EMBL; AK291907; BAF84596.1; -; mRNA.
DR EMBL; CH471126; EAW57032.1; -; Genomic_DNA.
DR EMBL; BC001180; AAH01180.1; -; mRNA.
DR EMBL; BC000125; AAH00125.1; -; mRNA.
DR EMBL; BC022242; AAH22242.1; -; mRNA.
DR EMBL; M38449; AAA36735.1; -; mRNA.
DR PIR; A27513; WFHU2.
DR RefSeq; NP_000651.3; NM_000660.5.
DR UniGene; Hs.645227; -.
DR PDB; 1KLA; NMR; -; A/B=279-390.
DR PDB; 1KLC; NMR; -; A/B=279-390.
DR PDB; 1KLD; NMR; -; A/B=279-390.
DR PDB; 3KFD; X-ray; 3.00 A; A/B/C/D=279-390.
DR PDBsum; 1KLA; -.
DR PDBsum; 1KLC; -.
DR PDBsum; 1KLD; -.
DR PDBsum; 3KFD; -.
DR ProteinModelPortal; P01137; -.
DR SMR; P01137; 30-390.
DR DIP; DIP-5934N; -.
DR IntAct; P01137; 18.
DR MINT; MINT-6806111; -.
DR STRING; 9606.ENSP00000221930; -.
DR BindingDB; P01137; -.
DR ChEMBL; CHEMBL1795178; -.
DR DrugBank; DB00070; Hyaluronidase.
DR PhosphoSite; P01137; -.
DR DMDM; 135674; -.
DR OGP; P01137; -.
DR PaxDb; P01137; -.
DR PRIDE; P01137; -.
DR DNASU; 7040; -.
DR Ensembl; ENST00000221930; ENSP00000221930; ENSG00000105329.
DR GeneID; 7040; -.
DR KEGG; hsa:7040; -.
DR UCSC; uc002oqh.2; human.
DR CTD; 7040; -.
DR GeneCards; GC19M041837; -.
DR H-InvDB; HIX0015152; -.
DR HGNC; HGNC:11766; TGFB1.
DR HPA; CAB000361; -.
DR MIM; 131300; phenotype.
DR MIM; 190180; gene.
DR neXtProt; NX_P01137; -.
DR Orphanet; 1328; Camurati-Engelmann disease.
DR Orphanet; 586; Cystic fibrosis.
DR PharmGKB; PA350; -.
DR eggNOG; NOG279949; -.
DR HOGENOM; HOG000290198; -.
DR HOVERGEN; HBG074115; -.
DR InParanoid; P01137; -.
DR KO; K13375; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR SignaLink; P01137; -.
DR ChiTaRS; TGFB1; human.
DR EvolutionaryTrace; P01137; -.
DR GeneWiki; TGF_beta_1; -.
DR GenomeRNAi; 7040; -.
DR NextBio; 27507; -.
DR PRO; PR:P01137; -.
DR ArrayExpress; P01137; -.
DR Bgee; P01137; -.
DR CleanEx; HS_TGFB1; -.
DR Genevestigator; P01137; -.
DR GO; GO:0030424; C:axon; IEA:Ensembl.
DR GO; GO:0009986; C:cell surface; IMP:BHF-UCL.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0005578; C:proteinaceous extracellular matrix; ISS:UniProtKB.
DR GO; GO:0005114; F:type II transforming growth factor beta receptor binding; IDA:BHF-UCL.
DR GO; GO:0046732; P:active induction of host immune response by virus; TAS:Reactome.
DR GO; GO:0002460; P:adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains; IEA:Ensembl.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0006754; P:ATP biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0060751; P:branch elongation involved in mammary gland duct branching; IEA:Ensembl.
DR GO; GO:0007050; P:cell cycle arrest; IDA:BHF-UCL.
DR GO; GO:0016049; P:cell growth; IEA:InterPro.
DR GO; GO:0045216; P:cell-cell junction organization; IDA:BHF-UCL.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; IEA:Ensembl.
DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; IEA:Ensembl.
DR GO; GO:0071407; P:cellular response to organic cyclic compound; IDA:UniProtKB.
DR GO; GO:0002062; P:chondrocyte differentiation; IDA:UniProtKB.
DR GO; GO:0007182; P:common-partner SMAD protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0002248; P:connective tissue replacement involved in inflammatory response wound healing; TAS:BHF-UCL.
DR GO; GO:0009817; P:defense response to fungus, incompatible interaction; IEA:Ensembl.
DR GO; GO:0048565; P:digestive tract development; IEA:Ensembl.
DR GO; GO:0009790; P:embryo development; IEA:Ensembl.
DR GO; GO:0007492; P:endoderm development; IEA:Ensembl.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0001837; P:epithelial to mesenchymal transition; IEA:Ensembl.
DR GO; GO:0019049; P:evasion or tolerance of host defenses by virus; IDA:BHF-UCL.
DR GO; GO:0085029; P:extracellular matrix assembly; IDA:BHF-UCL.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:BHF-UCL.
DR GO; GO:0060325; P:face morphogenesis; IEA:Ensembl.
DR GO; GO:0007565; P:female pregnancy; IEA:Ensembl.
DR GO; GO:0060364; P:frontal suture morphogenesis; IEA:Ensembl.
DR GO; GO:0008354; P:germ cell migration; IEA:Ensembl.
DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IDA:UniProtKB.
DR GO; GO:0030214; P:hyaluronan catabolic process; IDA:UniProtKB.
DR GO; GO:0048839; P:inner ear development; IEA:Ensembl.
DR GO; GO:0070306; P:lens fiber cell differentiation; IEA:Ensembl.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0048535; P:lymph node development; ISS:UniProtKB.
DR GO; GO:0010742; P:macrophage derived foam cell differentiation; IC:BHF-UCL.
DR GO; GO:0060744; P:mammary gland branching involved in thelarche; IEA:Ensembl.
DR GO; GO:0000165; P:MAPK cascade; IMP:UniProtKB.
DR GO; GO:0007093; P:mitotic cell cycle checkpoint; IDA:BHF-UCL.
DR GO; GO:0032943; P:mononuclear cell proliferation; IEA:Ensembl.
DR GO; GO:0042552; P:myelination; IEA:Ensembl.
DR GO; GO:0043011; P:myeloid dendritic cell differentiation; IEA:Ensembl.
DR GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IDA:BHF-UCL.
DR GO; GO:0030308; P:negative regulation of cell growth; IDA:BHF-UCL.
DR GO; GO:0022408; P:negative regulation of cell-cell adhesion; IDA:BHF-UCL.
DR GO; GO:0008156; P:negative regulation of DNA replication; IMP:BHF-UCL.
DR GO; GO:0050680; P:negative regulation of epithelial cell proliferation; IDA:BHF-UCL.
DR GO; GO:0045599; P:negative regulation of fat cell differentiation; IDA:UniProtKB.
DR GO; GO:1900126; P:negative regulation of hyaluronan biosynthetic process; IDA:UniProtKB.
DR GO; GO:0050777; P:negative regulation of immune response; IEA:Ensembl.
DR GO; GO:0010936; P:negative regulation of macrophage cytokine production; IDA:DFLAT.
DR GO; GO:0045930; P:negative regulation of mitotic cell cycle; IDA:BHF-UCL.
DR GO; GO:0045662; P:negative regulation of myoblast differentiation; IDA:UniProtKB.
DR GO; GO:0007406; P:negative regulation of neuroblast proliferation; IEA:Ensembl.
DR GO; GO:0030279; P:negative regulation of ossification; IEA:Ensembl.
DR GO; GO:0050765; P:negative regulation of phagocytosis; IEA:Ensembl.
DR GO; GO:0001933; P:negative regulation of protein phosphorylation; IDA:BHF-UCL.
DR GO; GO:0051280; P:negative regulation of release of sequestered calcium ion into cytosol; IEA:Ensembl.
DR GO; GO:0048642; P:negative regulation of skeletal muscle tissue development; IDA:UniProtKB.
DR GO; GO:0042130; P:negative regulation of T cell proliferation; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-dependent; IDA:UniProtKB.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; TAS:Reactome.
DR GO; GO:0031100; P:organ regeneration; IEA:Ensembl.
DR GO; GO:0043932; P:ossification involved in bone remodeling; IEP:BHF-UCL.
DR GO; GO:0060389; P:pathway-restricted SMAD protein phosphorylation; IDA:BHF-UCL.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; IDA:BHF-UCL.
DR GO; GO:0030501; P:positive regulation of bone mineralization; IEP:BHF-UCL.
DR GO; GO:0090190; P:positive regulation of branching involved in ureteric bud morphogenesis; IEA:Ensembl.
DR GO; GO:0071158; P:positive regulation of cell cycle arrest; IEA:Ensembl.
DR GO; GO:0051781; P:positive regulation of cell division; IEA:UniProtKB-KW.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IDA:BHF-UCL.
DR GO; GO:0050921; P:positive regulation of chemotaxis; IDA:BHF-UCL.
DR GO; GO:0032967; P:positive regulation of collagen biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; IDA:BHF-UCL.
DR GO; GO:0031536; P:positive regulation of exit from mitosis; IEA:Ensembl.
DR GO; GO:0010763; P:positive regulation of fibroblast migration; IDA:BHF-UCL.
DR GO; GO:0035066; P:positive regulation of histone acetylation; IEA:Ensembl.
DR GO; GO:0031065; P:positive regulation of histone deacetylation; IEA:Ensembl.
DR GO; GO:0032740; P:positive regulation of interleukin-17 production; IDA:BHF-UCL.
DR GO; GO:0048298; P:positive regulation of isotype switching to IgA isotypes; IDA:MGI.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:BHF-UCL.
DR GO; GO:1901666; P:positive regulation of NAD+ ADP-ribosyltransferase activity; IDA:BHF-UCL.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IEA:Ensembl.
DR GO; GO:0042482; P:positive regulation of odontogenesis; IEA:Ensembl.
DR GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; IDA:BHF-UCL.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; IDA:BHF-UCL.
DR GO; GO:0031334; P:positive regulation of protein complex assembly; IDA:BHF-UCL.
DR GO; GO:0035307; P:positive regulation of protein dephosphorylation; IDA:BHF-UCL.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling cascade; IDA:BHF-UCL.
DR GO; GO:0050714; P:positive regulation of protein secretion; IDA:BHF-UCL.
DR GO; GO:0060391; P:positive regulation of SMAD protein import into nucleus; IDA:BHF-UCL.
DR GO; GO:0051152; P:positive regulation of smooth muscle cell differentiation; IEA:Ensembl.
DR GO; GO:0032930; P:positive regulation of superoxide anion generation; IDA:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
DR GO; GO:2000679; P:positive regulation of transcription regulatory region DNA binding; IDA:BHF-UCL.
DR GO; GO:0010575; P:positive regulation vascular endothelial growth factor production; TAS:BHF-UCL.
DR GO; GO:0006611; P:protein export from nucleus; IDA:UniProtKB.
DR GO; GO:0000060; P:protein import into nucleus, translocation; IDA:UniProtKB.
DR GO; GO:0043491; P:protein kinase B signaling cascade; IMP:UniProtKB.
DR GO; GO:0032801; P:receptor catabolic process; IDA:BHF-UCL.
DR GO; GO:0060762; P:regulation of branching involved in mammary gland duct morphogenesis; IEA:Ensembl.
DR GO; GO:0061035; P:regulation of cartilage development; IEA:Ensembl.
DR GO; GO:0002028; P:regulation of sodium ion transport; IEA:Ensembl.
DR GO; GO:0045066; P:regulatory T cell differentiation; IEA:Ensembl.
DR GO; GO:0070723; P:response to cholesterol; IDA:BHF-UCL.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0032355; P:response to estradiol stimulus; IDA:BHF-UCL.
DR GO; GO:0009749; P:response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0034616; P:response to laminar fluid shear stress; IEA:Ensembl.
DR GO; GO:0032570; P:response to progesterone stimulus; IDA:BHF-UCL.
DR GO; GO:0009314; P:response to radiation; IEA:Ensembl.
DR GO; GO:0033280; P:response to vitamin D; IEA:Ensembl.
DR GO; GO:0007435; P:salivary gland morphogenesis; IEP:BHF-UCL.
DR GO; GO:0007183; P:SMAD protein complex assembly; IDA:BHF-UCL.
DR GO; GO:0007184; P:SMAD protein import into nucleus; IDA:BHF-UCL.
DR GO; GO:0043029; P:T cell homeostasis; IEA:Ensembl.
DR GO; GO:0002513; P:tolerance induction to self antigen; IEA:Ensembl.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0001657; P:ureteric bud development; IEA:Ensembl.
DR GO; GO:0019058; P:viral life cycle; TAS:Reactome.
DR InterPro; IPR001839; TGF-b_C.
DR InterPro; IPR001111; TGF-b_N.
DR InterPro; IPR016319; TGF-beta.
DR InterPro; IPR015615; TGF-beta-rel.
DR InterPro; IPR003939; TGFb1.
DR InterPro; IPR017948; TGFb_CS.
DR PANTHER; PTHR11848; PTHR11848; 1.
DR Pfam; PF00019; TGF_beta; 1.
DR Pfam; PF00688; TGFb_propeptide; 1.
DR PIRSF; PIRSF001787; TGF-beta; 1.
DR PRINTS; PR01423; TGFBETA.
DR PRINTS; PR01424; TGFBETA1.
DR SMART; SM00204; TGFB; 1.
DR PROSITE; PS00250; TGF_BETA_1; 1.
DR PROSITE; PS51362; TGF_BETA_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cleavage on pair of basic residues; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Extracellular matrix; Glycoprotein; Growth factor; Mitogen;
KW Polymorphism; Reference proteome; Secreted; Signal.
FT SIGNAL 1 29
FT CHAIN 30 278 Latency-associated peptide.
FT /FTId=PRO_0000033762.
FT CHAIN 279 390 Transforming growth factor beta-1.
FT /FTId=PRO_0000033763.
FT REGION 30 74 Straightjacket domain (By similarity).
FT REGION 75 271 Arm domain (By similarity).
FT MOTIF 244 246 Cell attachment site (Potential).
FT CARBOHYD 82 82 N-linked (GlcNAc...).
FT CARBOHYD 136 136 N-linked (GlcNAc...) (By similarity).
FT CARBOHYD 176 176 N-linked (GlcNAc...) (By similarity).
FT DISULFID 33 33 Interchain (with C-1359 or C-1384 in
FT LTBP1); in inactive form (By similarity).
FT DISULFID 223 223 Interchain (with C-225) (By similarity).
FT DISULFID 225 225 Interchain (with C-223) (By similarity).
FT DISULFID 285 294
FT DISULFID 293 356
FT DISULFID 322 387
FT DISULFID 326 389
FT DISULFID 355 355 Interchain.
FT VARIANT 10 10 L -> P (associated with higher bone
FT mineral density and lower frequency of
FT vertebral fractures in Japanese post-
FT menopausal women; dbSNP:rs1800470).
FT /FTId=VAR_016171.
FT VARIANT 25 25 R -> P (in dbSNP:rs1800471).
FT /FTId=VAR_016172.
FT VARIANT 81 81 Y -> H (in CE; leads to TGF-beta-1
FT intracellular accumulation).
FT /FTId=VAR_017607.
FT VARIANT 218 218 R -> C (in CE; higher levels of active
FT TGF-beta-1 in the culture medium;
FT enhances osteoclast formation in vitro).
FT /FTId=VAR_017608.
FT VARIANT 218 218 R -> H (in CE).
FT /FTId=VAR_017609.
FT VARIANT 222 222 H -> D (in CE; sporadic case; higher
FT levels of active TGF-beta-1 in the
FT culture medium).
FT /FTId=VAR_017610.
FT VARIANT 223 223 C -> G (in CE).
FT /FTId=VAR_067303.
FT VARIANT 223 223 C -> R (in CE).
FT /FTId=VAR_067304.
FT VARIANT 225 225 C -> R (in CE; higher levels of active
FT TGF-beta-1 in the culture medium).
FT /FTId=VAR_017611.
FT VARIANT 263 263 T -> I (in dbSNP:rs1800472).
FT /FTId=VAR_016173.
FT CONFLICT 159 159 R -> RR (in Ref. 2; CAA26580).
FT HELIX 282 285
FT STRAND 291 296
FT STRAND 299 301
FT HELIX 302 306
FT STRAND 311 313
FT STRAND 315 318
FT STRAND 321 324
FT STRAND 330 332
FT HELIX 335 346
FT STRAND 347 349
FT STRAND 356 370
FT STRAND 373 389
SQ SEQUENCE 390 AA; 44341 MW; 75391614250288FE CRC64;
MPPSGLRLLL LLLPLLWLLV LTPGRPAAGL STCKTIDMEL VKRKRIEAIR GQILSKLRLA
SPPSQGEVPP GPLPEAVLAL YNSTRDRVAG ESAEPEPEPE ADYYAKEVTR VLMVETHNEI
YDKFKQSTHS IYMFFNTSEL REAVPEPVLL SRAELRLLRL KLKVEQHVEL YQKYSNNSWR
YLSNRLLAPS DSPEWLSFDV TGVVRQWLSR GGEIEGFRLS AHCSCDSRDN TLQVDINGFT
TGRRGDLATI HGMNRPFLLL MATPLERAQH LQSSRHRRAL DTNYCFSSTE KNCCVRQLYI
DFRKDLGWKW IHEPKGYHAN FCLGPCPYIW SLDTQYSKVL ALYNQHNPGA SAAPCCVPQA
LEPLPIVYYV GRKPKVEQLS NMIVRSCKCS
//

MIM 131300
*RECORD*
*FIELD* NO
131300
*FIELD* TI
#131300 CAMURATI-ENGELMANN DISEASE; CAEND
;;CED;;
ENGELMANN DISEASE;;
DIAPHYSEAL DYSPLASIA 1, PROGRESSIVE; DPD1;;
read morePROGRESSIVE DIAPHYSEAL DYSPLASIA; PDD
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
Camurati-Engelmann disease results from domain-specific heterozygous
mutations in the transforming growth factor-beta-1 gene (TGFB1; 190180)
on chromosome 19q13. Also see Camurati-Engelmann disease type 2 (606631)
in which no mutation in the TGFB1 gene has been found.

DESCRIPTION

Camurati-Engelmann disease is a rare autosomal dominant type of bone
bone dysplasia. The hallmark of the disorder is the cortical thickening
of the diaphyses of the long bones. Hyperostosis is bilateral and
symmetrical and usually starts at the diaphyses of the femora and
tibiae, expanding to the fibulae, humeri, ulnae, and radii. As the
disease progresses, the metaphyses may be affected as well, but the
epiphyses are spared. Sclerotic changes at the skull base may be
present. The onset of the disease is usually during childhood and almost
always before the age of 30. Most patients present with limb pain,
muscular weakness, a waddling gait, and easy fatigability. Systemic
manifestations such as anemia, leukopenia, and hepatosplenomegaly occur
occasionally (summary by Janssens et al., 2006).

CLINICAL FEATURES

Camurati (1922) of Bologna described a rare type of 'symmetrical
hereditary osteitis' involving the lower limbs in a father and son and
several others in a total of 4 generations. Pain in the legs and
fusiform swelling of the legs below the knees were noted. Engelmann
(1929) of Vienna reported an isolated case of 'osteopathica
hyperostotica (sclerotisans) multiplex infantilis.' The disorder is
sometimes called Camurati-Engelmann disease in recognition of the
earlier description. Cockayne (1920) described a probable case before
the publications of Camurati and Engelmann. The nature of the condition
and the possibility that it represented syphilitic osteitis were
discussed.

Lennon et al. (1961) described a case of Engelmann disease and reviewed
the literature. Gross thickening of the cortex of bones, both on the
periosteal surface and in the medullary canal, is characteristic. The
process usually begins in the shaft of the femur or tibia but spreads to
involve all bones. Onset is usually before age 30 years, often before
age 10. All races and both sexes are affected. Nine examples of familial
occurrence in 1 or 2 generations were mentioned. Severe bone pains,
especially in the legs, and muscular hypoplasia are the distinctive
features of this form of sclerotic bone disease. The bones of the base
of the skull and rarely the mandible may be affected. The skeletal
disorder is often associated with muscular weakness, peculiar gait,
pains in the legs, fatigability, and apparent undernutrition. The
muscular weakness is not necessarily progressive and typical bone
changes may be found in asymptomatic persons. Because of the associated
features, muscular dystrophy or poliomyelitis is sometimes diagnosed in
these patients.

The condition described by Ribbing and in the past sometimes referred to
as Ribbing disease (601477) has been considered by some to be Engelmann
disease. Ribbing (1949) described a family in which 4 of 6 sibs were
affected. The diaphyseal osteosclerosis and hyperostosis were limited to
one or more (up to 4) of the long bones, the tibia being affected in
all. The father, who was dead, had complained for many years of pains in
the legs. Thus, the condition may be dominant; no x-ray studies of the
father were available and Ribbing (1949) noted that the body had been
cremated. Paul (1953) reported the same entity in 2 of 4 sibs, one of
whom also had otosclerosis, which was present in several other members
of the kindred. In an addendum, Paul noted that the infant son of one of
his patients had difficulty walking and was found to have multiple
sclerosing lesions of long bones. Again dominant inheritance was
suggested. Ribbing (1949) referred to the condition described as
hereditary multiple diaphyseal sclerosis (rather than dysplasia), and
the same term was used by Paul (1953) and Furia and Schwartz (1990).
Seeger et al. (1996) insisted that Ribbing disease is a disorder
separate from Engelmann disease. Although it may appear to be identical
radiographically, many clinical differences exist. Camurati-Engelmann
disease presents during childhood, whereas Ribbing disease was thought
by Seeger et al. (1996) to present in middle age. (They wrote: 'patients
contract Ribbing disease after puberty.') The disease is confined to the
diaphyses of long bones, especially the tibia and the femur. Whereas
Engelmann disease is bilateral and symmetric, Ribbing disease is either
unilateral or asymmetric and asynchronously bilateral. In Engelmann
disease, the skull is involved as well as the long bones. The gait and
neurologic abnormalities and anemia with extramedullary hematopoiesis
occurs only in Engelmann disease.

Makita et al. (2000) reported a 3-generation Japanese family with
Engelmann disease with a wide variation in phenotype among the affected
family members. Of the 12 patients, 7 had full manifestations of
Engelmann disease, while the other 5 exhibited only segmental
(rhizomelic and/or mesomelic) involvement and asymmetric diaphyseal
sclerosis without any clinical symptoms, resembling Ribbing disease. The
authors proposed that Engelmann disease and Ribbing disease represent
phenotypic variation of the same disorder.

Crisp and Brenton (1982) emphasized systemic manifestations in Engelmann
disease: anemia, leukopenia, hepatosplenomegaly, and raised erythrocyte
sedimentation rate. Their patient also had the Raynaud phenomenon and
multiple nail-fold infarcts.

Clybouw et al. (1994) reported a 10-year-old girl with characteristic
clinical and roentgenologic manifestations of Camurati-Engelmann
disease. Scintigraphy with 99mTc showed increased osteoblastic activity
in the diaphyseal portions of almost all long bones. Clinical and
roentgenologic investigations of her parents produced normal results,
but a clear focus of osteoblastic hyperactivity was demonstrated
scintigraphically at the base of the skull of the proband's mother. Some
persons with Camurati-Engelmann disease may have subclinical
manifestations. According to Clybouw et al. (1994), a detailed study
including x-ray examination and scintigraphy is necessary for genetic
counseling in apparently sporadic cases.

Grey et al. (1996) provided a 45-year follow-up on a patient with
Engelmann disease initially described by Stronge and McDowell (1950)
when he was 28 years of age. The disease had shown progression over the
subsequent 45 years, characterized by the unique involvement of the
femoral capital epiphyses. The patient had changed little in physical
appearance, apart from aging. He was thin and tall with generalized
underdevelopment and weakness of the muscles, particularly around the
pelvic girdle and thighs. The legs were bowed and the lumbar lordosis
had increased. Serum alkaline phosphatase levels had remained normal. In
1950 the disease involved only the diaphyses of the affected limbs. By
45 years later it had affected the metaphyses of all limbs, the
epiphyses, and the articular surfaces of the femoral heads and
acetabula, as well as the right tibial epiphysis. The spine and hands,
unaffected in 1950, showed changes and there was some progression of the
disease in the skull.

Saraiva (2000) described anticipation as judged by age of onset of
symptoms in successive generations of a large family with 15 affected
members in 3 generations.

Wallace et al. (2004) reported a 4-generation pedigree with 7
individuals affected by CED. The pedigree demonstrated autosomal
dominant inheritance but with remarkable variation in expressivity and
reduced penetrance. The most severely affected individual had
progression of mild skull hyperostosis to severe skull thickening and
cranial nerve compression over 30 years. His carrier father, on the
other hand, remained asymptomatic into his ninth decade and had no
radiographic hyperostosis or sclerosis of the bones. Symptomatic
relatives presented with lower limb pain and weakness. They were
initially diagnosed with a variety of other conditions. Two of the
symptomatic individuals were treated successfully with prednisone.
Linkage to 19q13.1-q13.3 was confirmed. The arg218-to-his mutation in
the TGFB1 gene (R218H; 190180.0003) was identified in the affected
individuals, the asymptomatic obligate carrier, and in another
unaffected relative.

Janssens et al. (2006) reported 41 individuals with CED confirmed by
genetic analysis from 14 families and provided a detailed review of the
disorder.

INHERITANCE

Girdany (1959) described a family with 6 affected persons in 3
generations (no male-to-male transmission). A case reported by Singleton
et al. (1956) had strikingly similar clinical features. Restudy
indicated that 3 generations were affected in that family also
(Singleton, 1967). Father and 2 children (son and daughter) were
affected in a family reported by Ramon and Buchner (1966). The father
was much more severely affected than the offspring. Allen et al. (1970)
presented a family in which 11 persons in 3 generations were known to
have been affected. Sparkes and Graham (1972) reported a remarkable
family with many affected persons in several successive generations. A
particularly remarkable feature was lack of penetrance in persons who
must have had the gene but, as adults at any rate, showed no abnormality
by x-ray.

CLINICAL MANAGEMENT

The beneficial effects of corticosteroids were apparently first
described by Royer et al. (1967), followed shortly by Allen et al.
(1970) and by Lindstrom (1974). Minford et al. (1981) noted not only
relief from pain but also return of radiologic findings toward normal
during treatment with corticosteroids.

POPULATION GENETICS

Campos-Xavier et al. (2001) stated that 5 mutations in the TGFB1 gene
had been identified in 21 families with CED. In 1 Australian family and
6 European families with CED, they found 3 of these mutations, R218H
(190180.0002) in 1 family, R218C (190180.0003) in 3 families, and C225R
(190180.0001) in 3 families, which had previously been observed in
families of Japanese and Israeli origin. The R218C mutation appeared to
be the most prevalent worldwide, having been found in 17 of 28 reported
families.

HETEROGENEITY

Campos-Xavier et al. (2001) found no obvious correlation between the
nature of TGFB1 mutations and the severity of the clinical
manifestations of CED, but observed a marked intrafamilial clinical
variability, supporting incomplete penetrance of CED.

Xavier et al. (2000) suggested that DPD1 is genetically homogeneous;
however, Hecht et al. (2001) excluded the TGFB1 gene as the site of
mutation in a DPD1 family, thus indicating the existence of at least one
other form.

Also see Camurati-Engelmann disease type II (606631) in which no
mutation in the TGFB1 gene has been found.

MAPPING

Ghadami et al. (2000) performed a genomewide linkage analysis of 2
unrelated Japanese families with CED, in which a total of 27 members
were available for study; 16 of them were affected with CED. Two-point
linkage analysis showed a maximum lod score of 7.41 (recombination
fraction 0.00; penetrance = 1.00) for the D19S918 microsatellite marker
locus. Haplotype analysis revealed that all the affected individuals
shared a common haplotype observed, in each family, between D19S881 and
D19S606, at 19q13.1-q13.3 (within a genetic interval of 15.1 cM). This
linkage was confirmed by Janssens et al. (2000) and Vaughn et al.
(2000).

MOLECULAR GENETICS

Because the transforming growth factor-beta-1 gene (TGFB1; 190180) maps
to the same region of chromosome 19, Kinoshita et al. (2000) screened it
for mutations in Camurati-Engelmann disease in 7 unrelated Japanese
families and 2 families of European descent. They detected 3 different
heterozygous missense mutations in exon 4, near the carboxy terminus of
the latency-associated peptide (LAP), in all 9 families examined.

*FIELD* SA
Clawson and Loop (1964); Hundley and Wilson (1973); Yoshioka et al.
(1980)
*FIELD* RF
1. Allen, D. T.; Saunders, A. M.; Northway, W. H., Jr.; Williams,
G. F.; Schafer, I. A.: Corticosteroids in the treatment of Engelmann's
disease: progressive diaphyseal dysplasia. Pediatrics 46: 523-531,
1970.

2. Campos-Xavier, A. B.; Saraiva, J. M.; Savarirayan, R.; Verloes,
A.; Feingold, J.; Faivre, L.; Munnich, A.; Le Merrer, M.; Cormier-Daire,
V.: Phenotypic variability at the TGF-beta-1 locus in Camurati-Engelmann
disease. Hum. Genet. 109: 653-658, 2001.

3. Camurati, M.: Di uno raro caso di osteite simmetrica ereditaria
degli arti inferiori. Chir. Organi Mov. 6: 662-665, 1922.

4. Clawson, D. K.; Loop, J. W.: Progressive diaphyseal dysplasia
(Engelmann's disease). J. Bone Joint Surg. Am. 46: 143-150, 1964.

5. Clybouw, C.; Desmyttere, S.; Bonduelle, M.; Piepsz, A.: Camurati-Engelmann
disease: contribution of bone scintigraphy to genetic counseling. Genet.
Counsel. 5: 195-198, 1994.

6. Cockayne, E. A.: Case for diagnosis. Proc. Roy. Soc. Med. 13:
132-136, 1920.

7. Crisp, A. J.; Brenton, D. P.: Engelmann's disease of bone--a systemic
disorder? Ann. Rheum. Dis. 41: 183-188, 1982.

8. Engelmann, G.: Ein Fall von Osteopathia hyperostotica (sclerotisans)
multiplex infantilis. Fortschr. Geb. Roentgenstr. Nukl. 39: 1101-1106,
1929.

9. Furia, J. P.; Schwartz, H. S.: Hereditary multiple diaphyseal
sclerosis: a tumor simulator. Orthopedics 13: 1267-1274, 1990.

10. Ghadami, M.; Makita, Y.; Yoshida, K.; Nishimura, G.; Fukushima,
Y.; Wakui, K.; Ikegawa, S.; Yamada, K.; Kondo, S.; Niikawa, N.; Tomita,
H.: Genetic mapping of the Camurati-Engelmann disease locus to chromosome
19q13.1-q13.3. Am. J. Hum. Genet. 66: 143-147, 2000. Note: Erratum:
Am. J. Hum. Genet. 66: 753 only, 2000.

11. Girdany, B. R.: Engelmann's disease (progressive diaphyseal dysplasia)--a
nonprogressive familial form of muscular dystrophy with characteristic
bone changes. Clin. Orthop. 14: 102-109, 1959.

12. Grey, A. C.; Wallace, R.; Crone, M.: Engelmann's disease: a 45-year
follow-up. J. Bone Joint Surg. Br. 78: 488-491, 1996.

13. Hecht, J. T.; Blanton, S. H.; Broussard, S.; Scott, A.; Hall,
C. R.; Milunsky, J. M.: Evidence for locus heterogeneity in the Camurati-Engelmann
(DPD1) syndrome. (Letter) Clin. Genet. 59: 198-200, 2001.

14. Hundley, J. D.; Wilson, F. C.: Progressive diaphyseal dysplasia:
review of the literature and report of seven cases in one family. J.
Bone Joint Surg. 55A: 461-474, 1973.

15. Janssens, K.; Gershoni-Baruch, R.; Van Hul, E.; Brik, R.; Guanabens,
N.; Migone, N.; Verbruggen, L. A.; Ralston, S. H.; Bonduelle, M.;
Van Maldergem, L.; Vanhoenacker, F.; Van Hul, W.: Localisation of
the gene causing diaphyseal dysplasia Camurati-Engelmann to chromosome
19q13. J. Med. Genet. 37: 245-249, 2000.

16. Janssens, K.; Vanhoenacker, F.; Bonduelle, M.; Verbruggen, L.;
Van Maldergem, L.; Ralston, S.; Guanabens, N.; Migone, N.; Wientroub,
S.; Divizia, M. T.; Bergmann, C.; Bennett, C.; Simsek, S.; Melancon,
S.; Cundy, T.; Van Hul, W.: Camurati-Engelmann disease: review of
the clinical, radiological, and molecular data of 24 families and
implications for diagnosis and treatment. J. Med. Genet. 43: 1-11,
2006.

17. Kinoshita, A.; Saito, T.; Tomita, H.; Makita, Y.; Yoshida, K.;
Ghadami, M.; Yamada, K.; Kondo, S.; Ikegawa, S.; Nishimura, G.; Fukushima,
Y.; Nakagomi, T.; Saito, H.; Sugimoto, T.; Kamegaya, M.; Hisa, K.;
Murray, J. C.; Taniguchi, N.; Niikawa, N.; Yoshiura, K.: Domain-specific
mutations in TGFB1 result in Camurati-Engelmann disease. Nature Genet. 26:
19-20, 2000.

18. Lennon, E. A.; Schechter, M. M.; Hornabrook, R. W.: Engelmann's
disease. Report of a case with review of the literature. J. Bone
Joint Surg. 43B: 273-284, 1961.

19. Lindstrom, J. A.: Diaphyseal dysplasia (Engelmann) treated with
corticosteroids. Birth Defects Orig. Art. Ser. X(12): 504-507, 1974.

20. Makita, Y.; Nishimura, G.; Ikegawa, S.; Ishii, T.; Ito, Y.; Okuno,
A.: Intrafamilial phenotypic variability in Engelmann disease (ED):
are ED and Ribbing disease the same entity? Am. J. Med. Genet. 91:
153-156, 2000.

21. Minford, A. M. B.; Hardy, G. J.; Forsythe, W. I.; Fitton, J. M.;
Rowe, V. L.: Engelmann's disease and the effect of corticosteroids:
a case report. J. Bone Joint Surg. Br. 63: 597-600, 1981.

22. Paul, L. W.: Hereditary multiple diaphyseal sclerosis (Ribbing). Radiology 60:
412-416, 1953.

23. Ramon, Y.; Buchner, A.: Camurati-Engelmann's disease affecting
the jaws. Oral Surg. 22: 592-599, 1966.

24. Ribbing, S.: Hereditary, multiple, diaphyseal sclerosis. Acta
Radiol. 31: 522-536, 1949.

25. Royer, P.; Vermeil, G.; Apostolides, P.; Engelmann, F.: Maladie
d'Engelmann: resultat du traitement par la prednisone. Arch. Franc.
Pediat. 24: 693-702, 1967.

26. Saraiva, J. M.: Anticipation in progressive diaphyseal dysplasia.
(Letter) J. Med. Genet. 37: 394-395, 2000.

27. Seeger, L. L.; Hewel, K. C.; Yao, L.; Gold, R. H.; Mirra, J. M.;
Chandnani, V. P.; Eckardt, J. J.: Ribbing disease (multiple diaphyseal
sclerosis): imaging and differential diagnosis. Am. J. Roentgen. 167:
689-694, 1996.

28. Singleton, E. B.: Personal Communication. Houston, Tex. 1967.

29. Singleton, E. B.; Thomas, J. R.; Worthington, W. W.; Hild, J.
R.: Progressive diaphyseal dysplasia (Engelmann's disease). Radiology 67:
233-240, 1956.

30. Sparkes, R. S.; Graham, C. B.: Camurati-Engelmann disease. Genetics
and clinical manifestations with a review of the literature. J. Med.
Genet. 9: 73-85, 1972.

31. Stronge, R. F.; McDowell, H. B.: A case of Engelmann's disease:
progressive diaphysial dysplasia. J. Bone Joint Surg. Br. 32: 38-39,
1950.

32. Vaughn, S. P.; Broussard, S.; Hall, C. R.; Scott, A.; Blanton,
S. H.; Milunsky, J. M.; Hecht, J. T.: Confirmation of the mapping
of the Camurati-Engelmann locus to 19q13.2 and refinement to a 3.2-cM
region. Genomics 66: 119-121, 2000.

33. Wallace, S. E.; Lachman, R. S.; Mekikian, P. B.; Bui, K. K.; Wilcox,
W. R.: Marked phenotypic variability in progressive diaphyseal dysplasia
(Camurati-Engelmann disease): report of a four-generation pedigree,
identification of a mutation in TGFB1, and review. Am. J. Med. Genet. 129A:
235-247, 2004.

34. Xavier, A. B. C. F.; Saraiva, J. M.; Le Merrer, M.; Dagoneau,
N.; Huber, C.; Penet, C.; Munnich, A.; Cormier-Daire, V.: Genetic
homogeneity of the Camurati-Engelmann disease. (Letter) Clin. Genet. 58:
150-152, 2000.

35. Yoshioka, H.; Mino, M.; Kiyosawa, N.; Hirasawa, Y.; Morikawa,
Y.; Kasubuchi, Y.; Kusunoki, T.: Muscular changes in Engelmann's
disease. Arch. Dis. Child. 55: 716-719, 1980.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Other];
Asthenic habitus

HEAD AND NECK:
[Ears];
Deafness;
[Eyes];
Exophthalmos;
Optic nerve compression;
Diplopia;
[Teeth];
Dental caries

SKELETAL:
[Skull];
Sclerosis of skull base;
Mandible involvement;
[Spine];
Sclerosis of posterior part of vertebrae (body and arches);
Scoliosis;
[Limbs];
Progressive diaphyseal widening;
Thickened cortices;
Narrowing of medullary canal;
Erlenmeyer flask defect;
Genu varus deformity;
Genu valgum deformity

MUSCLE, SOFT TISSUE:
Relative muscle weakness, especially in pelvic girdle;
Atrophic muscle fiber on biopsy

NEUROLOGIC:
[Central nervous system];
Headaches

ENDOCRINE FEATURES:
Delayed puberty

HEMATOLOGY:
Bone marrow hypoplasia;
Anemia

MISCELLANEOUS:
Waddling gait;
Leg pain;
Onset in childhood

MOLECULAR BASIS:
Caused by mutations in the beta-1 transforming growth factor gene
(TGFB1, 190180.0001)

*FIELD* CN
Kelly A. Przylepa - revised: 7/9/2001

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

*FIELD* ED
joanna: 07/02/2013
joanna: 2/2/2009
joanna: 7/9/2001
alopez: 11/3/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 2/10/2006
Victor A. McKusick - updated: 9/22/2004
Victor A. McKusick - updated: 1/17/2002
Carol A. Bocchini - reorganized: 1/16/2002
Victor A. McKusick - updated: 8/2/2001
Michael J. Wright - updated: 7/20/2001
Victor A. McKusick - updated: 8/28/2000
Sonja A. Rasmussen - updated: 4/24/2000
Victor A. McKusick - updated: 1/3/2000
Iosif W. Lurie - updated: 7/17/1996

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

*FIELD* ED
carol: 07/10/2012
carol: 12/7/2011
terry: 12/7/2011
carol: 12/6/2011
terry: 1/13/2011
wwang: 2/28/2006
ckniffin: 2/10/2006
tkritzer: 9/23/2004
terry: 9/22/2004
carol: 1/31/2002
carol: 1/24/2002
terry: 1/17/2002
carol: 1/16/2002
mcapotos: 12/26/2001
mcapotos: 12/21/2001
mcapotos: 8/13/2001
terry: 8/2/2001
alopez: 7/27/2001
terry: 7/20/2001
terry: 10/11/2000
terry: 9/28/2000
alopez: 8/28/2000
terry: 8/28/2000
mcapotos: 5/3/2000
terry: 4/24/2000
carol: 3/30/2000
terry: 2/10/2000
mcapotos: 1/5/2000
terry: 1/3/2000
terry: 4/30/1999
terry: 6/5/1998
jamie: 10/25/1996
mark: 10/23/1996
terry: 10/7/1996
mark: 10/3/1996
terry: 9/9/1996
carol: 7/17/1996
mimadm: 9/24/1994
davew: 6/27/1994
carol: 9/27/1993
carol: 4/7/1992
supermim: 3/16/1992
carol: 3/4/1992

MIM 190180
*RECORD*
*FIELD* NO
190180
*FIELD* TI
*190180 TRANSFORMING GROWTH FACTOR, BETA-1; TGFB1
;;TGF-BETA; TGFB
*FIELD* TX

DESCRIPTION
read more
TGFB is a multifunctional peptide that controls proliferation,
differentiation, and other functions in many cell types. TGFB acts
synergistically with TGFA (190170) in inducing transformation. It also
acts as a negative autocrine growth factor. Dysregulation of TGFB
activation and signaling may result in apoptosis. Many cells synthesize
TGFB and almost all of them have specific receptors for this peptide.
TGFB1, TGFB2 (190220), and TGFB3 (190230) all function through the same
receptor signaling systems.

CLONING

Using oligonucleotide probes designed from a partial amino acid sequence
of TGFB1 purified from blood platelets, Derynck et al. (1985) cloned
TGFB1 from a genomic library derived from human term placenta mRNA. The
deduced precursor protein contains 391 amino acids, of which the
C-terminal 112 amino acids constitute the mature protein. An arg-arg
dipeptide precedes the proteolytic cleavage site. The TGFB1 precursor
contains 3 potential N-glycosylation sites. Northern blot analysis
detected a 2.5-kb transcript in all solid tumors of meso-, endo- and
ectoblastic origin tested and in tumors cell lines of hematopoietic
origin. The transcript was also detected in normal peripheral blood
lymphocytes and placenta; it was not detected in liver, although it was
expressed by a hepatoma cell line. Nonreduced purified TGFB from human
blood platelets showed an apparent molecular mass of about 25 kD. Under
reducing conditions, it migrated with an apparent molecular mass of 12.5
kD, indicating that TGFB consists of 2 polypeptide chains linked by
intermolecular disulfide bridges.

GENE STRUCTURE

Derynck et al. (1987) determined that the TGFB1 precursor gene contains
7 exons and very large introns.

MAPPING

By somatic cell hybridization and in situ hybridization, Fujii et al.
(1985, 1986) assigned TGFB to 19q13.1-q13.3 in man and to chromosome 7
in the mouse. Dickinson et al. (1990) mapped the Tgfb1 gene to mouse
chromosome 7.

GENE FUNCTION

Dickinson et al. (1990) pointed out that high levels of TGFB1 mRNA
and/or protein have been localized in developing cartilage, endochondral
and membrane bone, and skin, suggesting a role in the growth and
differentiation of these tissues.

Dubois et al. (1995) demonstrated in vitro that pro-TGFB1 was cleaved by
furin (136950) to produce a biologically active TGFB1 protein.
Expression of pro-TGFB1 in furin-deficient cells produced no TGFB1,
whereas coexpression of pro-TGFB1 and furin led to processing of the
precursor.

Blanchette et al. (1997) showed that furin mRNA levels were increased in
rat synovial cells by the addition of TGFB1. This effect was eliminated
by pretreatment with actinomycin-D, suggesting to them that regulation
was at the gene transcription level. Treatment of rat synoviocytes and
kidney fibroblasts with TGFB1 or TGFB2 (190220) resulted in increased
pro-TGFB1 processing, as evidenced by the appearance of a 40-kD
immunoreactive band corresponding to the TGFB1 amino-terminal
pro-region. Treatment of these cells with TGFB2 resulted in a
significant increase in extracellular mature TGFB1. Blanchette et al.
(1997) concluded that TGFB1 upregulates gene expression of its own
converting enzyme.

Heldin et al. (1997) discussed mechanisms used by members of the
TGF-beta family to elicit their effects on target cells; see SMAD1
(601595).

SMAD proteins mediate TGFB signaling to regulate cell growth and
differentiation. Stroschein et al. (1999) proposed a model of regulation
of TGFB signaling by SnoN (165340) in which SnoN maintains the repressed
state of TGFB target genes in the absence of ligand and participates in
the negative feedback regulation of TGFB signaling. To initiate a
negative feedback mechanism that permits a precise and timely regulation
of TGFB signaling, TGFB also induces an increased expression of SnoN at
a later stage, which in turn binds to SMAD heteromeric complexes and
shuts off TGFB signaling.

Jang et al. (2001) determined that the human DAP-kinase (600831)
promoter is activated by TGFB through the action of SMAD2 (601366),
SMAD3 (603109), and SMAD4 (600993). Overexpression of DAP-kinase
triggers apoptosis in the absence of TGFB, whereas inhibition of
DAP-kinase activity protects cells from TGFB-induced apoptosis, blocks
TGFB-induced release of cytochrome c from mitochondria, and prevents
TGFB-induced dissipation of the mitochondrial membrane potential. Jang
et al. (2001) concluded that DAP-kinase mediates TGFB-dependent
apoptosis by linking SMADs to mitochondrial-based pro-apoptotic events.

Valderrama-Carvajal et al. (2002) studied the signaling pathway
activated by inhibin and TGFB1 during apoptosis in mouse and human
hematopoietic cell lines. They determined that the downstream effectors
include SMAD (see 601595) and SHIP (601582), a 5-prime inositol
phosphatase. Activation of the SMAD pathway induced SHIP expression,
resulting in intracellular changes in phospholipid pools and inhibited
phosphorylation of protein kinase B (AKT1; 164730).

Lin et al. (2004) demonstrated that cytoplasmic PML (102578) is an
essential modulator of TGF-beta signaling. Primary cells from Pml-null
mice are resistant to TGF-beta-dependent growth arrest, induction of
cellular senescence, and apoptosis. These cells also have impaired
phosphorylation and nuclear translocation of the TGF-beta signaling
proteins Smad2 and Smad3, as well as impaired induction of TGF-beta
target genes. Expression of cytoplasmic Pml is induced by TGF-beta.
Furthermore, cytoplasmic Pml physically interacts with Smad2, Smad3, and
SMAD anchor for receptor activation (SARA; 603755), and is required for
association of Smad2 and Smad3 with Sara and for the accumulation of
Sara and TGF-beta receptor in the early endosome. The PML-RAR-alpha
(180240) oncoprotein of acute promyelocytic leukemia can antagonize
cytoplasmic PML function, and acute promyelocytic leukemia cells have
defects in TGF-beta signaling similar to those observed in Pml-null
cells. Lin et al. (2004) concluded that their findings identified
cytoplasmic PML as a critical TGF-beta receptor and further implicated
deregulated TGF-beta signaling in cancer pathogenesis.

Using primary human hematopoietic cells and microarray analysis,
Scandura et al. (2004) identified p57(KIP2) (600856) as the only
cyclin-dependent kinase inhibitor induced by TGF-beta. Upregulation of
p57 mRNA and protein occurred before TGF-beta-induced G1 cell cycle
arrest, required transcription, and was mediated via a highly conserved
region of the proximal p57 promoter. Upregulation of p57 was essential
for TGF-beta-induced cell cycle arrest in these cells, since 2 different
small interfering RNAs that prevented p57 upregulation blocked the
cytostatic effects of TGF-beta on the hematopoietic cells.

Jobling et al. (2004) found that Tbgf1, Tgfb2, and Tgfb3 were expressed
in scleral tissue and scleral fibroblasts of tree shrew pups. All 3
isoforms increased collagen production in scleral fibroblasts in a
dose-dependent manner, and changes in Tgfb expression were observed
during development of experimental myopia in these animals.

Shehata et al. (2004) found increased levels of TGFB1 in bone marrow,
serum, and plasma of 13 patients with hairy cell leukemia compared to
controls and patients with B-cell leukemia. In vitro studies showed that
the hairy cells were the main source of TGFB1 mRNA. TGFB1 levels
correlated with bone marrow fibrosis and infiltration of hairy cells.
Bone marrow plasma from patients increased the synthesis of type I (see
120150) and type III (see 120180) procollagens at the mRNA and protein
levels, and this fibrogenic activity was abolished by anti-TGFB1
antibodies. Shehata et al. (2004) concluded that TGFB1 is directly
involved in the pathogenesis of bone marrow reticulin fibrosis in hairy
cell leukemia.

Using real-time RT-PCR, immunofluorescence microscopy, flow cytometry,
and immunohistochemistry, Liu et al. (2006) found that cultured mouse
neurons expressed Tgfb and B7 (CD80; 112203). Neuron-T cell interaction
led to upregulation of Tgfb, B7, B7.2 (CD86; 601020), and Tgfbr2
(190182) expression in neurons, which could be inhibited by blockade of
Tnf (191160) and Ifng (147570) in T cells. Furthermore, neuron-T cell
interaction increased expression of Zap70 (176947), Il2 (147680), and
Il9 (146931) in T cells. T-cell proliferation was dependent on neuronal
Tgfb and B7. Stimulation of encephalitogenic T-cell lines with neurons
induced Tgfb, Tgfbr2, and Smad3 expression and resulted in conversion of
the cells to a regulatory T-cell (Treg) phenotype expressing Tgfb, Ctla4
(123890), and Foxp3 (300292). These Treg cells were capable of
suppressing encephalitogenic T cells and inhibited experimental
autoimmune encephalomyelitis in vivo. Blocking the B7 and Tgfb pathways
prevented central nervous system (CNS)-specific generation of Treg
cells. Liu et al. (2006) concluded that neurons induce generation of
Treg cells in the CNS that are instrumental in regulating CNS
inflammation.

Cordenonsi et al. (2007) found that RTK/Ras/MAPK activity induces p53
(191170) N-terminal phosphorylation, enabling the interaction of p53
with the TGF-beta-activated SMADs. This mechanism confined mesoderm
specification in Xenopus embryos and promoted TGF-beta cytostasis in
human cells. Cordenonsi et al. (2007) concluded that these data
indicated a mechanism to allow extracellular cues to specify the
TGF-beta gene expression program.

TGF-beta converts naive T cells into regulatory T cells that prevent
autoimmunity. However, in the presence of IL6 (147620), TGF-beta also
promotes the differentiation of naive T lymphocytes into proinflammatory
IL17 (603149) cytokine-producing T helper-17 (Th17) cells, which promote
autoimmunity and inflammation. This raises the question of how TGF-beta
can generate such distinct outcomes. Mucida et al. (2007) identified the
vitamin A metabolite retinoic acid as a key regulator of
TGF-beta-dependent immune responses, capable of inhibiting the
IL6-driven induction of proinflammatory Th17 cells and promoting
antiinflammatory regulatory T cell (Treg) differentiation. Mucida et al.
(2007) concluded that a common metabolite can regulate the balance
between pro- and antiinflammatory immunity.

Yang et al. (2008) confirmed that whereas IL1-beta (147720) and IL6
induce IL17A secretion from human central memory CD4+ T cells, TGF-beta
and IL21 (605384) uniquely promote the differentiation of human naive
CD4+ T cells into Th17 cells accompanied by expression of the
transcription factor RORC2 (see 602943).

Veldhoen et al. (2008) found that Tgfb could reprogram Th2 cells to lose
their characteristic profile and switch to IL9 secretion. In combination
with Il4 (147780), Tgfb could directly drive the generation of
Il9-producing T cells, or Th9 cells. Veldhoen et al. (2008) concluded
that TGFB is a cytokine that influences, or fine tunes, fate decisions
of T cells depending on the presence of other cytokines.

Using flow cytometric analysis, Casetti et al. (2009) demonstrated that,
like alpha-beta T cells, gamma-delta cells can also function as Tregs
that express FOXP3 when stimulated with phosphoantigen in the presence
of TGFB1 and IL15 (600554).

Wandzioch and Zaret (2009) investigated how bone morphogenetic protein
(BMP4; 112262), TGF-beta, and fibroblast growth factor signaling
pathways converge on the earliest genes that elicit pancreas and liver
induction in mouse embryos. These genes include ALB1 (103600), PROX1
(601546), HNF6 (604164), HNF1B (189907), and PDX1 (600733). The
inductive network was found to be dynamic; it changed within hours.
Different signals functioned in parallel to induce different early
genes, and 2 permutations of signals induced liver progenitor domains,
which revealed flexibility in cell programming. Also, the specification
of pancreas and liver progenitors was restricted by the TGF-beta
pathway.

Ghoreschi et al. (2010) showed that Th17 differentiation can occur in
the absence of TGF-beta signaling. Neither IL6 nor IL23 (see 605580)
alone efficiently generated Th17 cells; however, these cytokines in
combination with IL1-beta effectively induced IL17 production in naive
precursors, independently of TGF-beta. Epigenetic modification of the
IL17A, IL17F (606496), and RORC promoters proceeded without TGF-beta-1,
allowing the generation of cells that coexpressed ROR-gamma-t (encoded
by RORC) and Tbet (TBX21; 604895). Tbet+ROR-gamma-t+Th17 cells are
generated in vivo during experimental allergic encephalomyelitis, and
adoptively transferred Th17 cells generated with IL23 without TGF-beta-1
were pathogenic in this disease model. Ghoreschi et al. (2010) concluded
that their data indicated an alternative mode for Th17 differentiation
and that, consistent with genetic data linking IL23R (607562) with
autoimmunity, their findings reemphasized the importance of IL23 and
therefore may have therapeutic implications.

Luo et al. (2010) showed that TGF-beta signaling is involved in
reproductive aging and germline quality control in C. elegans. Data
generated from oocyte array studies suggested that TGF-beta is also
involved in reproductive aging in humans and mice.

- Role in Duchenne Muscular Dystrophy

Using quantitative PCR in 15 cases of Duchenne muscular dystrophy (DMD;
310200) and 13 cases of Becker muscular dystrophy (BMD; 300376), as well
as 11 spinal muscular atrophy patients (SMA; 253300) and 16 controls,
Bernasconi et al. (1995) found that TGFB1 expression as measured by mRNA
was greater in DMD and BMD patients than in controls. Fibrosis was
significantly more prominent in DMD than in BMD, SMA, or controls. The
proportion of connective tissue biopsies increased progressively with
age in DMD patients, while TGFB1 levels peaked at 2 and 6 years of age.
Bernasconi et al. (1995) concluded that expression of TGFB1 in the early
stages of DMD may be critical in initiating muscle fibrosis, and
suggested that antifibrosis treatment might slow progression of the
disease, increasing the utility of gene therapy.

- Role in Kidney Disease

Although transforming growth factor-beta plays a central role in tissue
repair, this cytokine is, as pointed out by Border and Noble (1995), a
double-edged sword with both therapeutic and pathologic potential.
TGF-beta has been implicated also in the pathogenesis of adult
respiratory distress syndrome (Shenkar et al., 1994), and the kidney
seems to be particularly sensitive to TGF-beta-induced fibrogenesis.
TGF-beta has been implicated as a cause of fibrosis in most forms of
experimental and human kidney disease (Border and Noble, 1994).

As reviewed by Reeves and Andreoli (2000), transforming growth
factor-beta contributes to progressive diabetic nephropathy (603933).
Renal failure is a common and serious complication of longstanding
diabetes mellitus, both type I (IDDM; 222100) and type II (NIDDM;
125853). The prognosis of diabetic nephropathy is very poor. Structural
abnormalities include hypertrophy of the kidney, an increase in the
thickness of glomerular basement membranes, and accumulation of
extracellular matrix components in the glomerulus, resulting in nodular
and diffuse glomerulosclerosis. The extent of matrix accumulation in
both the glomeruli and interstitium correlates strongly with the degree
of renal insufficiency and proteinuria. TGF-beta appears to play a role
in the development of renal hypertrophy and accumulation of
extracellular matrix in diabetes. It is known to have powerful
fibrogenic actions. In both humans and animal models, TGF-beta mRNA and
protein levels are significantly increased in the glomeruli and
tubulointerstitium in diabetes. Sharma et al. (1996) found that
short-term administration of TGF-beta neutralizing antibodies to rats
with chemically induced diabetes prevented glomerular enlargement and
suppressed the expression of genes encoding extracellular matrix
components.

Further strong indications of the role of TGF-beta were provided by
Ziyadeh et al. (2000), who tested whether chronic administration of
anti-TGF-beta antibody could prevent renal insufficiency and
glomerulosclerosis in the db/db mouse, a model of type II diabetes that
develops overt nephropathy. They found that treatment with the antibody,
but not with IgG, significantly decreased plasma TGF-beta-1
concentration without decreasing plasma glucose concentration.
Furthermore, it prevented the increase in plasma creatinine
concentration, the decrease in urinary creatinine clearance, and the
expansion of mesangial matrix in db/db mice. The increase in renal
matrix mRNA of COL4A1 (120130) and fibronectin (135600) was
substantially attenuated; on the other hand, urinary excretion of
albumin was not significantly affected by the treatment. Chen et al.
(2003) found that treatment with anti-TGFB antibody partly reversed
glomerular basement membrane thickening and mesangial matrix
accumulation in db/db mice.

As to the downstream targets of TGF-beta that mediate the
pathophysiology of diabetic nephropathy, Waldegger et al. (1999)
identified a serine/threonine kinase, serum/glucocorticoid-regulated
kinase (SGK; 602958) that is transcriptionally upregulated by TGF-beta
in both macrophage and liver cell experimental systems. Lang et al.
(2000) demonstrated that excessive extracellular glucose concentrations
enhance SGK transcription, which in turn stimulates renal tubular sodium
ion transport.

Azar et al. (2000) compared the levels of TGF-beta in the serum of
groups of patients with IDDM and NIDDM divided according to the duration
of their disease. Twenty-six normoalbuminuric patients with IDDM and 25
normoalbuminuric patients with NIDDM were divided into 3 groups
according to the onset of their diabetes and were compared with 27 and
15 age-matched normal subjects, respectively. The authors concluded that
in normoalbuminuric patients serum TGF-beta levels increased at the
onset of NIDDM and remained elevated throughout the disease. They did
not change at the onset of IDDM, however, and started to decrease around
2 years after the onset of the disease.

Also see MOLECULAR GENETICS section.

- Role in Cancer

Derynck et al. (2001) reviewed TGF-beta signaling in tumor suppression
and cancer progression. Of the 3 TGFBs, TGFB1 is most frequently
upregulated in tumor cells and is the focus of most studies on the role
of TGFB in tumorigenesis. The autocrine and paracrine effects of
TGF-beta on tumor cells and the tumor microenvironment exert both
positive and negative influences on cancer development. Derynck et al.
(2001) attempted to reconcile the positive and negative effects of
TGF-beta in carcinogenesis.

Using a synergistic transplantation system and a chronic myeloid
leukemia (CML)-like myeloproliferative disease mouse model, Naka et al.
(2010) showed that Foxo3a has an essential role in the maintenance of
CML leukemia-initiating cells (LIC). They found that cells with nuclear
localization of Foxo3a and decreased Akt (164730) phosphorylation are
enriched in the LIC population. Serial transplantation of LICs generated
from Foxo3a-wildtype and Foxo3a-null mice showed that the ability of
LICs to cause disease is significantly decreased by Foxo3a deficiency.
Furthermore, Naka et al. (2010) found that TGF-beta is a critical
regulator of Akt activation in LICs and controls Foxo3a localization. A
combination of TGF-beta inhibition, Foxo3a deficiency, and imatinib
treatment led to efficient depletion of CML in vivo. Furthermore, the
treatment of human CML LICs with a TGF-beta inhibitor impaired their
colony-forming ability in vitro. Naka et al. (2010) concluded that their
results demonstrate a critical role for the TGF-beta-FOXO pathway in the
maintenance of LICs.

Also see MOLECULAR GENETICS section.

- Role in Scleroderma

Scleroderma (see 181750) is a chronic systemic disease that leads to
fibrosis of the skin and other affected organs. TGFB has been implicated
in the pathogenesis of scleroderma. SMAD proteins function as signaling
transducers downstream from TGFB receptors. Dong et al. (2002)
investigated the signaling components of the TGFB pathway and TGFB
activity in scleroderma lesions in vivo and in scleroderma fibroblasts
in vitro. Basal level and TGFB-inducible expression of SMAD7 (602932)
were selectively decreased, whereas SMAD3 (603109) expression was
increased both in scleroderma skin and in explanted scleroderma
fibroblasts in culture. TGFB signaling events were increased in
scleroderma fibroblasts relative to normal fibroblasts. In vitro
adenoviral gene transfer with SMAD7 restored normal TGFB signaling in
scleroderma fibroblasts. These results suggested that alterations in the
SMAD pathway, including marked SMAD7 deficiency and SMAD3 upregulation,
may be responsible for TGFB hyperresponsiveness observed in scleroderma.

- Role in Camurati-Engelmann Disease

See MOLECULAR GENETICS section.

- Role in Lung Disease

Munger et al. (1999) showed that the TGFB1 latency-associated peptide
(LAP) is a ligand for the integrin alpha-V-beta-6 (see 193210 and
147558) and that alpha-V-beta-6-expressing cells induce spatially
restricted activation of TGF-beta-1. They suggested that their finding
explains why mice lacking this integrin develop exaggerated inflammation
and, as they showed, are protected from pulmonary fibrosis. Pittet et
al. (2001) showed that integrin alpha-V-beta-6 activates latent TGFB in
the lungs and skin. They also showed that mice lacking this integrin are
completely protected from pulmonary edema in a model of
bleomycin-induced acute lung injury. Pharmacologic inhibition of TGFB
also protected wildtype mice from pulmonary edema induced by bleomycin
or E. coli endotoxin. TGFB directly increased alveolar epithelial
permeability in vitro by a mechanism that involved depletion of
intracellular glutathione. Pittet et al. (2001) concluded that
integrin-mediated local activation of TGFB is critical to the
development of pulmonary edema in acute lung injury and that blocking
TGFB or its activation could be effective treatments.

- Role in Obesity

Long et al. (2003) noted that increased expression and a polymorphism of
TGFB1 had been associated with abdominal obesity and body mass index
(BMI) in humans. They investigated the association of TGFB1 and APOE
(107741) with obesity by analyzing several SNPs of each gene in 1,873
subjects from 405 white families to test for linkage or association with
4 obesity phenotypes including BMI, fat mass, percentage fat mass (PFM),
and lean mass, with the latter 3 being measured by dual energy x-ray
absorptiometry. A significant linkage disequilibrium (p less than 0.01)
was observed between pairs of SNPs within each gene except for SNP5 and
SNP6 in TGFB1 (p greater than 0.01). Within-family association was
observed in the APOE gene for SNP1 and PFM (p = 0.001) and for the CGTC
haplotype with both fat mass (p = 0.012) and PFM (p = 0.006). For the
TGFB1 gene, within-family association was found between lean mass and
SNP5 (p = 0.003), haplotype C+C (p = 0.12), and haplotype T+C (p =
0.012). Long et al. (2003) concluded that the large study size,
analytical method, and inclusion of the lean mass phenotype improved the
power of their study and explained discrepancies in previous studies,
and that both APOE and TGFB1 are associated with obesity phenotypes in
their population.

- Role in Cardiac Fibrosis

Zeisberg et al. (2007) showed that cardiac fibrosis is associated with
the emergence of fibroblasts originating from endothelial cells,
suggesting an endothelial-mesenchymal transition (EndMT) similar to
events that occur during formation of the atrioventricular cushion in
the embryonic heart. TGFB1 induced endothelial cells to undergo EndMT,
whereas bone morphogenic protein-7 (BMP7; 112267) preserved the
endothelial phenotype. The systemic administration of recombinant human
BMP7 significantly inhibited EndMT and the progression of cardiac
fibrosis in mouse models of pressure overload and chronic allograft
rejection. Zeisberg et al. (2007) concluded that EndMT contributes to
the progression of cardiac fibrosis and that recombinant human BMP7 can
be used to inhibit EndMT and to intervene in the progression of chronic
heart disease associated with fibrosis.

Davis et al. (2008) demonstrated that induction of a contractile
phenotype in human vascular smooth muscle cells by TGF-beta and BMPs is
mediated by miR21 (611020). miR21 downregulates PDCD4 (608610), which in
turn acts as a negative regulator of smooth muscle contractile genes.
Surprisingly, TGF-beta and BMP signaling promoted a rapid increase in
expression of mature miR21 through a posttranscriptional step, promoting
the processing of primary transcripts of miR21 (pri-miR21) into
precursor miR21 (pre-miR21) by the Drosha complex (608828). TGF-beta and
BMP-specific SMAD signal transducers SMAD1 (601595), SMAD2 (601366),
SMAD3, (603109), and SMAD5 (603110) are recruited to pri-miR21 in a
complex with the RNA helicase p68 (DDX5; 180630), a component of the
Drosha microprocessor complex. The shared cofactor SMAD4 (600993) is not
required for this process. Thus, Davis et al. (2008) concluded that
regulation of microRNA biogenesis by ligand-specific SMAD proteins is
critical for control of the vascular smooth muscle cell phenotype and
potentially for SMAD4-independent responses mediated by the TGF-beta and
BMP signaling pathways.

- Role in Marfan Syndrome

Selected manifestations of Marfan syndrome (MFS; 154700) reflect
excessive signaling by the TGF-beta family of cytokines. Habashi et al.
(2006) showed that aortic aneurysm in a mouse model of Marfan syndrome
is associated with increased TGF-beta signaling and can be prevented by
TGF-beta antagonists such as TGF-beta-neutralizing antibody or the
angiotensin II type 1 receptor (AGTR1; 106165) blocker, losartan.

Gelb (2006) discussed the mechanism by which TGF-beta interacts with the
extracellular matrix and the role of fibrillin (134797), mutation in
which causes Marfan syndrome.

Matt et al. (2009) found that circulating total TGFB1 levels were
significantly higher in patients with Marfan syndrome than controls (p
less than 0.0001), and Marfan syndrome patients treated with losartan or
beta-blocker showed significantly lower total TGFB1 concentrations
compared with untreated Marfan syndrome patients (p = 0.03 to 0.05).
However, the authors did not observe a close correlation between
circulating TGFB1 levels and aortic root size or Z scores. Matt et al.
(2009) concluded that TGFB1 levels might serve as a prognostic or
therapeutic marker in Marfan syndrome.

BIOCHEMICAL FEATURES

- Crystal Structure

Shi et al. (2011) determined the crystal structure of pro-TGF-beta-1 at
3.05-angstrom resolution. Crystals of dimeric porcine pro-TGF-beta-1
revealed a ring-shaped complex, a novel fold for the prodomain, and
showed how the prodomain shields the growth factor from recognition by
receptors and alters its conformation. Complex formation between
alpha-V-beta-6 integrin (see 193210) and the prodomain is insufficient
for TGF-beta-1 release. Force-dependent activation requires unfastening
of a 'straitjacket' that encircles each growth factor monomer at a
position that can be locked by a disulfide bond. Sequences of all 33
TGF-beta family members indicated a similar prodomain fold.

MOLECULAR GENETICS

In a study of 170 pairs of female twins (average age 57.7 years),
Grainger et al. (1999) showed that the concentration of active plus
acid-activatable latent TGFB1 is predominantly under genetic control
(heritability estimate 0.54). SSCP mapping of the TGFB1 gene promoter
identified 2 single-base substitution polymorphisms. The 2 polymorphisms
(G to A at position -800 bp and C to T at position -509 bp) are in
linkage disequilibrium. The -509C-T polymorphism (dbSNP rs1800469) was
significantly associated with plasma concentration of active plus
acid-activatable latent TGFB1, which explained 8.2% of the additive
genetic variance in the concentration. Grainger et al. (1999) suggested,
therefore, that predisposition to atherosclerosis, bone diseases, or
various forms of cancer may be correlated with the presence of
particular alleles at the TGFB1 locus.

The -509C-T (-1347C-T) SNP of the TGFB1 gene results in increased plasma
levels of TGF-beta-1. Shah et al. (2006) demonstrated that the
difference in TGFB1 levels was due to transcriptional suppression by AP1
(see 165160) binding to wildtype -1347C. In vitro and in vivo cellular
studies showed that an AP1 complex containing JunD (165162) and c-Fos
(164810) was recruited to the TGFB1 promoter only when the -1347C allele
was present. Thus, increased TGF-beta-1 levels are associated with the
-1347T allele because of the loss of negative regulation by AP1. Shah et
al. (2006) also found that HIF1A (603348) bound to a site that overlaps
the AP1 binding site surrounding -1347, suggesting that the 2
transcription factors compete for binding to -1347C.

African Americans (blacks) have a higher incidence and prevalence of
hypertension and hypertension-associated target organ damage compared
with Caucasian Americans (whites). Suthanthiran et al. (2000) explored
the hypotheses that TGFB1 is hyperexpressed in hypertensives compared
with normotensives and that TGFB1 overexpression is more frequent in
blacks than in whites. These hypotheses were stimulated by the
demonstration that TGFB1 is hyperexpressed in blacks with end-stage
renal disease compared with white end-stage renal disease patients
(Suthanthiran et al., 1998; Li et al., 1999) and by the biologic
attributes of TGFB1, which include induction of endothelin-1 expression,
stimulation of renin release, and promotion of vascular and renal
disease when TGFB1 is produced in excess. Suthanthiran et al. (2000)
determined TGFB1 profiles in black and white hypertensive subjects and
normotensive controls and included circulating protein concentrations,
mRNA steady-state levels, and codon 10 genotype. They showed that TGFB1
protein levels are highest in black hypertensives, and TGFB1 protein as
well as TGFB1 mRNA levels are higher in hypertensives compared with
normotensives. The proline allele at codon 10 was more frequent in
blacks compared with whites, and its presence was associated with higher
levels of TGFB1 mRNA and protein. The findings of Suthanthiran et al.
(2000) supported the idea that TGFB1 hyperexpression is a risk factor
for hypertension and hypertensive complications and provided a mechanism
for the excess burden of hypertension in blacks.

Blobe et al. (2000) reviewed the role of TGFB in human disease. Many
aspects of cancer involve mutations in the TGF-beta pathway. Two forms
of hereditary hemorrhagic telangiectasia (HHT1, 187300; HHT2, 600376)
has been shown to be caused by mutations in the genes for 2 receptors in
the TGF-beta family, endoglin (ENG; 131195) and ALK1 (601284). There is
also evidence that TGF-beta, when overexpressed, has a role in fibrotic
disease. The authors cited the description by Awad et al. (1998) of a
polymorphism of the TGFB1 gene that increases the production of
TGF-beta-1 and is associated with the development of fibrotic lung
disease.

Watanabe et al. (2002) identified 106 SNPs and 11 other types of
variations in TGFB1 and 6 other genes: TGFBR1 (190181), TGFBR2 (190182),
SMAD2 (601366), SMAD3, SMAD4 (600993), and SMAD7, all of which are part
of the TGF-beta-1 signaling pathway. Watanabe et al. (2002) also
estimated allele frequencies of these DNA polymorphisms among 48
Japanese individuals.

Celedon et al. (2004) performed association analysis between SNPs in the
TGFB1 gene and chronic obstructive pulmonary disease (COPD; 606963)
phenotypes in a family-based sample and a case-control study.
Stratification by smoking status substantially improved the evidence of
linkage to chromosome 19q for COPD phenotypes. Among former and current
smokers in the study, there was significant evidence of linkage (lod =
3.30) between chromosome 19q and prebronchodilator (pre-BD) forced
expiratory volume at 1 second (FEV1). In these families, 3 SNPs in TGFB1
were significantly associated with pre- and post-BD FEV1 (p less than
0.05). Among smokers in the COPD cases and control subjects, 3 SNPs in
TGFB1 were significantly associated with COPD (p less than or equal to
0.02 in all cases). Celedon et al. (2004) concluded that chromosome 19q
likely contains a genetic locus (or loci) that influences COPD through
an interaction with cigarette smoking.

Shah et al. (2006) reported a comprehensive examination of function and
diversity for the regulatory region of TGFB1, including an expanded
promoter region and exon 1 (-2665 to +423). The authors identified
strong enhancer activity for a distal promoter segment (-2665 to -2205).
Ten novel polymorphisms and 14 novel alleles were identified among 38
unrelated racially diverse samples, and many of the SNPs were unique to
persons of African descent. In vitro functional assays of 2 of the
variants, -1287G-A (dbSNP rs11466314) and -387C-T (dbSNP rs11466315),
showed differences in reporter gene expression.

Phillips et al. (2008) studied SNP genotypes of TGF-beta in BMPR2
(600799) mutation carriers with pulmonary hypertension (178600) and
examined the age of diagnosis and penetrance of the pulmonary
hypertension phenotype. BMPR2 heterozygotes with least active -509 or
codon 10 TGFB1 SNPs had later mean age at diagnosis of familial
pulmonary arterial hypertension (39.5 and 43.2 years, respectively) than
those with more active genotypes (31.6 and 33.1 years, P = 0.03 and
0.02, respectively). Kaplan-Meier analysis showed that those with less
active SNPs had later age at diagnosis. BMPR2 mutation heterozygotes
with nonsense-mediated decay-resistant BMPR2 mutations and the least,
intermediate, and most active -509 TGFB1 SNP phenotypes had penetrances
of 33%, 72%, and 80%, respectively (P = 0.003), whereas those with 0-1,
2, or 3-4 active SNP alleles had penetrances of 33%, 72%, and 75% (P =
0.005). Phillips et al. (2008) concluded that the TGFB1 SNPs studied
modulate age at diagnosis and penetrance of familial pulmonary arterial
hypertension in BMPR2 mutation heterozygotes, likely by affecting
TGFB/BMP signaling imbalance. The authors considered this modulation an
example of synergistic heterozygosity.

- Camurati-Engelmann Disease

Camurati-Engelmann disease (CED; 131300) is an autosomal dominant,
progressive diaphyseal dysplasia characterized by hyperostosis and
sclerosis of the diaphyses of long bones. This disorder was mapped to
19q13.1-q13.3, making TGFB1 a candidate for the site of the causative
mutations. Kinoshita et al. (2000) screened the TGFB1 gene for mutations
in affected members of 7 unrelated Japanese families and 2 families of
European descent. They detected 3 different heterozygous missense
mutations in exon 4, near the carboxy terminus of the latency-associated
peptide (LAP), in all 9 families examined. All mutation sites in the 9
CED patients were located either at (C225) or near (R218) the S-S bonds
in LAP, suggesting the importance of this region in activating
TGF-beta-1 in the bone matrix. Noteworthy, arginine at 218 and cysteine
at 225 are highly conserved from chicken to human, and hydropathy plots
indicated that all 3 mutations affect the dimerization of LAP,
consequently altering the conformation of the domain structure.

Janssens et al. (2000) also reported 4 different mutations of the TGFB1
gene in 6 families with Camurati-Engelmann disease.

Campos-Xavier et al. (2001) stated that 5 mutations in the TGFB1 gene
had been identified in 21 families with CED. In 1 Australian family and
6 European families with CED, they found 3 of these mutations, R218H
(190180.0002) in 1 family, R218C (190180.0003) in 3 families, and C225R
(190180.0001) in 3 families, which had previously been observed in
families of Japanese and Israeli origin. The R218C mutation appeared to
be the most prevalent worldwide, having been found in 17 of 28 reported
families. Campos-Xavier et al. (2001) found no obvious correlation
between the nature of the mutations and the severity of the clinical
manifestations, but observed a marked intrafamilial clinical
variability, supporting incomplete penetrance of CED.

Kinoshita et al. (2000) identified 3 mutations in the TGFB1 gene in
patients with CED. They commented that studies of the role of TGF-beta
in modeling and/or remodeling bone tissue were conflicting. Whether the
3 mutations they observed result in hyperactivation of TGF-beta-1 or its
early degradation in vivo leading to insufficient signal transduction
remained to be investigated.

Janssens et al. (2003) stated that a total of 7 different mutations in
TGFB1 had been found as the cause of CED. They investigated the effects
of 5 of these on the functioning of TGF-beta-1 in vitro. A luciferase
reporter assay specific for TGF-beta-induced transcriptional response
showed that all 5 mutations increased TGF-beta-1 activity. In 3 of the
mutations, this effect was caused by an increase in active TGF-beta-1 in
the medium of the transfected cells. The other 2 mutations had a
profound effect on secretion; a decreased amount of TGF-beta-1 was
secreted, but increased luciferase activity showed that an aberrant
intracellular accumulation of gene product could initiate an enhanced
transcriptional response, suggesting the existence of an alternative
signaling pathway. The data indicated that mutations in the signal
peptide and latency-associated peptide facilitate TGFB1 signaling, thus
causing Camurati-Engelmann disease.

Kinoshita et al. (2004) performed haplotype analysis of 13 unrelated CED
patients and found that at least 9 independent mutation events had
occurred (see, e.g., 190180.0005-190180.0006). They pointed out that
there are at least 3 'accumulation sites' of mutations in the TGFB1
gene: amino acid positions 218, 223, and 225. The cysteine residues at
these positions serve as disulfide bonds between 2 LAP molecules and
contribute to their dimerization.

ANIMAL MODEL

TGF-beta plays an important role in wound healing. A number of
pathologic conditions, such as idiopathic pulmonary fibrosis,
scleroderma, and keloids, which share the characteristic of fibrosis,
are associated with increased TGF-beta-1 expression. To evaluate the
role of TGF-beta-1 in the pathogenesis of fibrosis, Clouthier et al.
(1997) used a transgenic approach. They targeted the expression of a
constitutively active TGF-beta-1 molecule to liver, kidney, and white
and brown adipose tissue using the regulatory sequences of the rat
phosphoenolpyruvate carboxykinase gene (261650). In multiple lines,
targeted expression of the transgene caused severe fibrotic disease.
Fibrosis of the liver occurred with varying degrees in severity
depending upon the level of expression of the TGFB1 gene. Overexpression
of the transgene in kidney also resulted in fibrosis and glomerular
disease, eventually leading to complete loss of renal function. Severe
obstructive uropathy (hydronephrosis) was also observed in a number of
animals. Expression in adipose tissue resulted in a dramatic reduction
in total body white adipose tissue and a marked, though less severe,
reduction in brown adipose tissue, producing a lipodystrophy-like
syndrome. Introduction of the transgene into the ob/ob background (see
164160) suppressed the obesity characteristic of this mutation; however,
transgenic mutant mice developed severe hepato- and splenomegaly.
Clouthier et al. (1997) noted that the family of rare conditions known
collectively as the lipodystrophies (151660, 269700) are accompanied in
almost all forms by other abnormalities, including fatty liver and
cardiomegaly. Metabolic and endocrine abnormalities include either mild
or severe insulin resistance, hypertriglyceridemia, and a hypermetabolic
state.

Crawford et al. (1998) showed that thrombospondin-1 (188060) is
responsible for a significant proportion of the activation of TGFB1 in
vivo. Histologic abnormalities in young Tgfb1-null and
thrombospondin-1-null mice were strikingly similar in 9 organ systems.
Lung and pancreas pathologies similar to those observed in Tgfb1-null
animals could be induced in wildtype pups by systemic treatment with a
peptide that blocked the activation of TGFB1 by thrombospondin-1.
Although these organs produced little active TGFB1 in
thrombospondin-1-null mice, when pups were treated with a peptide
derived from thrombospondin-1 that could activate TGFB1, active cytokine
was detected in situ, and the lung and pancreatic abnormalities reverted
toward wildtype.

Wyss-Coray et al. (1997) found that aged transgenic mice with increased
astrocytic expression of TGFB1 showed increased deposition of the
beta-amyloid precursor protein (APP; 104760) in cerebral blood vessels
and meninges. Cerebral vessel amyloid deposition was further increased
in transgenic mice overexpressing APP, similar to the vascular changes
seen in patients with Alzheimer disease (AD; 104300) and cerebral
amyloid angiopathy (CAA). Postmortem analysis of 15 AD brains showed
increased TGFB1 immunoreactivity and increased TGFB1 mRNA, which
correlated with beta-amyloid deposition in damaged cerebral blood
vessels of patients with AD and CAA compared to AD patients without CAA
or normal controls. Wyss-Coray et al. (1997) concluded that glial
overexpression of TGFB1 may promote the deposition of cerebral vascular
beta-amyloid in AD-related amyloidosis.

TGFB1, a key regulator of the brain's responses to injury and
inflammation, has been implicated in amyloid-beta deposition in vivo.
Wyss-Coray et al. (2001) demonstrated that a modest increase in
astroglial TGFB1 production in aged transgenic mice expressing the human
APP (Games et al., 1995) results in a 3-fold reduction in the number of
parenchymal amyloid plaques, a 50% reduction in the overall amyloid-beta
load in the hippocampus and neocortex, and a decrease in the number of
dystrophic neurites. In mice expressing human APP and TGFB1,
amyloid-beta accumulated substantially in cerebral blood vessels, but
not in parenchymal plaques. In human cases of Alzheimer disease,
amyloid-beta immunoreactivity associated with parenchymal plaques was
inversely correlated with amyloid-beta in blood vessels and cortical
TGFB1 mRNA levels. The reduction of parenchymal plaques in APP/TGFB1
mice was associated with a strong activation of microglia and an
increase in inflammatory mediators. Recombinant TGFB1 stimulated
amyloid-beta clearance in microglial cell cultures. Wyss-Coray et al.
(2001) concluded that TGFB1 is an important modifier of amyloid
deposition in vivo and indicate that TGFB1 might promote microglial
processes that inhibit the accumulation of amyloid-beta in the brain
parenchyma.

Ikuno and Kazlauskas (2002) studied the role of TGFB1 in the tractional
retinal detachments of proliferative vitreoretinopathy in rabbits. Their
results showed that vitreous promoted cellular contraction, that TGFB1
was the major factor responsible, and that at least a portion of the
TGFB1-dependent contraction proceeded through platelet-derived growth
factor receptor-alpha (PDGFRA; 173490). They concluded that PDGFRA is
responsible for mediating cellular contraction of multiple growth
factors: TGFB1 and members of the PDGF family.

Thyagarajan et al. (2001) developed transgenic mice that overexpressed
Tgfb1 predominantly in odontoblasts. The transgene for targeted
expression was constructed by fusing the Dspp (125485) upstream
regulatory sequence to an active porcine Tgfb1 cDNA. The teeth of
transgenic mice expressing this construct showed a significant reduction
in tooth mineralization, defective dentin formation, and a relatively
high branching of dentinal tubules. Dentin extracellular matrix
components were increased and deposited abnormally in the dental pulp.
Expression of Dspp was significantly downregulated.

A subgroup of individuals with Marfan syndrome (154700), an autosomal
dominant disorder of connective tissue caused by mutations in
fibrillin-1 (FBN1; 134797), have distal airspace enlargement,
historically described as emphysema, which frequently results in
spontaneous lung rupture (pneumothorax). Neptune et al. (2003) showed
that mice deficient in fibrillin-1 have marked dysregulation of TGF-beta
activation and signaling, resulting in apoptosis in the developing lung.
Perinatal antagonism of TGF-beta by means of a TGF-beta-neutralizing
antibody attenuated apoptosis and rescued alveolar septation in vivo.
These data indicated that matrix sequestration of cytokines is crucial
to their regulated activation and signaling and that perturbation of
this function can contribute to the pathogenesis of disease. Kaartinen
and Warburton (2003) discussed the general implications of the finding
that fibrillin controls TGF-beta activation.

Ng et al. (2004) examined mitral valves from Fbn1-null mice and found
postnatally acquired alterations in architecture that correlated both
temporally and spatially with increased cell proliferation, decreased
apoptosis, and excess TGF-beta activation and signaling. TGF-beta
antagonism in vivo rescued the valve phenotype. Expression analyses
identified increased expression of numerous TGF-beta-related genes that
regulate cell proliferation and survival. Ng et al. (2004) suggested
that TGF-beta is a mediator of myxomatous mitral valve disease.

In Fbn1-deficient mice, Cohn et al. (2007) demonstrated that increased
TGF-beta activity resulted in failed muscle regeneration by inhibition
of satellite cell proliferation and differentiation. Systemic antagonism
of TGF-beta through administration of TGF-beta-neutralizing antibody or
the AGTR1 (106165) blocker losartan normalized muscle architecture,
repair, and function in vivo. In dystrophin (300377)-deficient mdx mice,
a model of Duchenne muscular dystrophy (310200), Cohn et al. (2007) also
demonstrated TGF-beta-induced failure of muscle regeneration and a
similar therapeutic response.

Matt et al. (2009) found that circulating total Tgfb1 levels in
Fbn1-deficient mice increased with age and were elevated compared to
age-matched wildtype mice. Losartan-treated Fbn1-null mice had lower
total Tgfb1 levels compared to age-matched Fbn1-null mice treated with
placebo, and circulating total Tgfb1 levels were indistinguishable from
those of age-matched wildtype mice. In addition, Matt et al. (2009)
observed a correlation between circulating Tgfb1 levels and aortic root
diameters in Fbn1-null and wildtype mice (p = 0.002).

Through a global analysis of pulmonary gene expression in the lungs of
mice lacking integrin beta-6 (ITGB6; 147558), Kaminski et al. (2000)
identified a marked induction of macrophage metalloelastase (MMP12;
601046), a metalloproteinase that preferentially degrades elastin and
has been implicated in the chronic lung disease emphysema. Morris et al.
(2003) demonstrated that Itgb6-null mice develop age-related emphysema
that is completely abrogated either by transgenic expression of versions
of the beta-6 integrin unit that support TGFB activation, or by the loss
of MMP12. Furthermore, Morris et al. (2003) showed that the effects of
ITGB6 deletion are overcome by simultaneous transgenic expression of
active TGFB1. Morris et al. (2003) concluded that they had uncovered a
pathway in which the loss of integrin-mediated activation of latent TGFB
causes age-dependent pulmonary emphysema through alterations of
macrophage MMP12 expression. Furthermore, they showed that a functional
alteration in the TGFB activation pathway affects susceptibility to this
disease.

Using transgenic mouse models, Siegel et al. (2003) examined the
influence of TGF-beta signaling on Neu (164870)-induced mammary
tumorigenesis and metastases. They generated mice expressing an
activated TGF-beta type I receptor (TGFBR1; 190181) or dominant-negative
TGF-beta type II receptor (TGFBR2; 190182) under control of the mouse
mammary tumor virus promoter. When crossed with mice expressing
activated forms of the Neu receptor tyrosine kinase that selectively
couple to the Grb2 (108355) or Shc (600560) signaling pathways, the
activated type I receptor increased the latency of mammary tumor
formation but also enhanced the frequency of extravascular lung
metastasis. Conversely, expression of the dominant-negative type II
receptor decreased the latency of Neu-induced mammary tumor formation
while significantly reducing the incidence of extravascular lung
metastases. These observations argued that TGF-beta can promote the
formation of lung metastases while impairing Neu-induced tumor growth
and suggested that extravasation of breast cancer cells from pulmonary
vessels is a point of action of TGF-beta in the metastatic process.

Sancho et al. (2003) analyzed a model of collagen-induced arthritis in
wildtype and Cd69 antigen (107273)-deficient mice and found that levels
of TGFB1 and TGFB2, which act as protective agents in collagen-induced
arthritis, were reduced in Cd69-null mice inflammatory foci, correlating
with an increase in proinflammatory cytokines. Local injection of
blocking anti-TGF antibodies increased arthritis severity and
proinflammatory cytokine mRNA levels in Cd69 wildtype but not null mice.
Sancho et al. (2003) concluded that CD69 is a negative modulator of
autoimmune reactivity and inflammation through the synthesis of TGFB1, a
cytokine that in turn downregulates the production of various
proinflammatory mediators.

Tang et al. (2003) identified a potent modifier locus on chromosome 1
(lod = 10.5), Tgfbkm2(129), that contributed over 90% of the genetic
component determining survival to birth (STB) of Tgfb1 -/- embryos in
crosses between C57 and 129 mice. Tgfb1 -/- STB also depended on
maternal effects. Fetal genotype and maternal factors interacted to
prevent Tgfb1 -/- embryonic death due to defective yolk sac
angiogenesis. C57 or C57/129 F1 mothers supported high Tgfb1 -/- STB
rates, whereas 129 mothers did not. Strain differences in circulating
maternal TGF-beta-1 levels were excluded as the cause of this
directional complementation; however, strong genetic support was evident
for the involvement of maternal STB alleles of mitochondrial or
imprinted genes that are only expressed when passed through the female
lineage.

Brionne et al. (2003) studied a mouse strain that survived to about 3
weeks of age in the absence of Tgfb1. These mice showed increased
numbers of apoptotic neurons, reduced neocortical presynaptic integrity,
reduced laminin (see 156225) expression, and widespread microgliosis.
Cultured primary neurons lacking Tgfb1 had reduced survival compared
with wildtype controls. Heterozygous knockout mice had normal life
spans, but they showed increased susceptibility to excitotoxic injury
and neurodegeneration. Transgenic overproduction of Tgfb1 prevented
degeneration after excitotoxic injury. Brionne et al. (2003) concluded
that TGFB1 has a nonredundant function in maintaining neuronal integrity
and survival of central nervous system neurons and in regulating
microglial activation.

Gao et al. (2004) generated mice with T cell-specific blockade of Tgfb1
signaling and found that the mice were completely insensitive to the
bone-sparing effect of estrogen. This insensitivity was accompanied by
upregulation of Ifng, which in turn led to increased T-cell activation
and T-cell Tnf production. Overexpression of Tgfb1 in vivo prevented
ovariectomy-induced bone loss. Gao et al. (2004) concluded that estrogen
prevents bone loss through a TGFB-dependent mechanism and that TGFB
signaling in T cells preserves bone homeostasis by blunting T-cell
activation.

TGFB1 is a potent keratinocyte growth inhibitor that is overexpressed in
keratinocytes in certain inflammatory skin diseases. Li et al. (2004)
found that transgenic mice expressing human TGFB1 in epidermis using a
keratin-5 (KRT5; 148040) promoter developed inflammatory skin lesions,
with gross appearance of psoriasis (see 177900)-like plaques,
generalized scaly erythema, and Koebner phenomenon, in which a
mechanical trauma induces or exacerbates psoriatic lesions. The lesions
were characterized by epidermal hyperproliferation, massive infiltration
of neutrophils, T lymphocytes, and macrophages to the epidermis and
superficial dermis, subcorneal microabscesses, basement membrane
degradation, and angiogenesis. Transgenic skin exhibited multiple
molecular changes that typically occur in T helper-1 (Th1) cell
inflammatory skin disorders, such as psoriasis. Further analysis
revealed enhanced SMAD signaling in transgenic epidermis and dermis. Li
et al. (2004) concluded that pathologic condition-induced TGFB1
overexpression in skin may synergize with or induce molecules required
for the development of Th1 inflammatory skin disorders.

Wurdak et al. (2005) inactivated the Tgfb gene in mouse neural crest
stem cells by targeted deletion. Mutants were recovered at the expected
mendelian frequency until embryonic day 18.5, but they died perinatally,
displaying multiple developmental defects, including mid/hindbrain
abnormalities. The mutant mice also showed several malformations seen in
patients with DiGeorge syndrome (188400), including malformations of
cranial bones and cartilage, cleft palate, hypoplastic parathyroid and
thymus glands, ventricular septal defect, truncus arteriosus, and
abnormal patterning of the arteries arising from the aortic arch. Wurdak
et al. (2005) found that Tgfb signaling in mouse neural crest cells was
necessary and sufficient for phosphorylation of Crkl (602007), a signal
adaptor implicated in the development of DiGeorge syndrome. Wurdak et
al. (2005) concluded that TGFB signaling may play a role in the etiology
of DiGeorge syndrome.

Han et al. (2005) found that human skin cancers frequently overexpress
TGFB1 but exhibit decreased expression of the TGF-beta type II receptor
(TGFBR2; 190182). In transgenic mouse models in which Tgfb1 expression
could be induced at specific stages of skin carcinogenesis in tumor
epithelia expressing a dominant-negative Tgfbr2, they observed that
late-stage Tgfb1 overexpression in chemically induced skin papillomas
did not exert a tumor-suppressive effect and that dominant-negative
Tgfbr2 expression selectively blocked Tgfb1-mediated
epithelial-to-mesenchymal transition but cooperated with Tgfb1 for tumor
invasion. Han et al. (2005) concluded that TGFB1 induces
epithelial-to-mesenchymal transition and invasion via distinct
mechanisms: TGFB1-mediated epithelial-to-mesenchymal transition requires
functional TGFBR, whereas TGFB1-mediated tumor invasion cooperates with
reduced TGFBR2 signaling in tumor epithelia.

In mice, Mao et al. (2006) identified a skin tumor susceptibility locus,
termed Skts14, containing the Tgfb1 gene on proximal chromosome 7.
Different polymorphic alleles at this locus resulting in differential
Tgfb1 gene expression altered skin tumor susceptibility. Moreover, fine
genetic mapping of different mouse strains showed that allelic variants
at the Skts14 locus interacted with the Skts15 tumor modifier locus on
chromosome 12 to drive papilloma susceptibility, indicating complex
genetic interactions in determining disease outcome.

Mangan et al. (2006) showed that exogenous Tgfb induced development of
proinflammatory Il17-producing T cells (Th17 cells) in Il12b (161561)
-/- mice, whose antigen-presenting cells produce neither Il12 or Il23.
In Ifng -/- T cells, Tgfb induced expression of Il23r (607562),
conferring Il23 responsiveness for Th17 cell development. Challenge of
Il12b -/- mice or Il23a (605580) -/- mice with a natural rodent
pathogen, Citrobacter rodentium, resulted in failure to clear infection
and death. In contrast to Il12b -/- mice, Il23a -/- mice did not show
impaired induction of an Il17 response. Histopathologic and flow
cytometric analysis demonstrated that intestinal tissue was enriched in
Th17 cells in wildtype mice, but not in Tgfb -/- mice; Tgfb +/- mice had
intermediate levels of Th17 cells. Activation of naive T cells with Tgfb
resulted in expression of both intracellular Il17 and Foxp3, a
transcription factor associated with Treg cells. Addition of Il6
(147620), however, nearly extinguished the Foxp3-positive cells. Mangan
et al. (2006) concluded that TGFB plays a dual role in T-cell
differentiation by directing distinct populations of FOXP3-positive Treg
cells and Th17 cells, contingent upon the inflammatory cytokine
environment.

Using mice with green fluorescent protein introduced into the endogenous
Foxp3 locus, Bettelli et al. (2006) found that Il6 completely inhibited
generation of Foxp3-positive Treg cells induced by Tgfb. The combination
of Il6 together with Tgfb induced differentiation of pathogenic Th17
cells from naive T cells. Bettelli et al. (2006) proposed that, in the
steady state or in the absence of an inflammatory insult, TGFB
suppresses induction of effector cells, such as Th1, Th2, or Th17 cells,
and induces FOXP3-positive Treg cells that maintain self tolerance.

Using in vitro and in vivo models, Tang et al. (2009) demonstrated that
active TGFB1 released during bone resorption coordinates bone formation
by inducing migration of bone mesenchymal stem cells to the bone
resorptive sites, and that this process is mediated through a SMAD (see
601595) signaling pathway. Tang et al. (2009) generated mice carrying
point mutations previously identified in patients with CED and observed
the typical progressive diaphyseal dysplasia seen in the human disease,
with high levels of active TGFB1 in the bone marrow. Treatment with a
TGFB1 receptor inhibitor partially rescued the uncoupled bone remodeling
and prevented fractures.

HISTORY

Gupta et al. (2006) retracted their paper describing the identification
of a microRNA in the latency-associated transcript (Lat) of herpes
simplex virus (HSV)-1 (miR-Lat) that targets TGFB and SMAD3 (603109) via
sequences in their 3-prime UTRs that show partial homology to miR-Lat.

*FIELD* AV
.0001
CAMURATI-ENGELMANN DISEASE
TGFB1, CYS225ARG

In a Japanese patient with Camurati-Engelmann disease (131300),
Kinoshita et al. (2000) found a 673T-C transition in the TGFB1 gene
resulting in a cys225-to-arg (C225R) missense mutation.

Janssens et al. (2000) found the C225R mutation in a family of European
descent.

Saito et al. (2001) demonstrated that the C225R mutation causes the
instability of the LAP homodimer and consequently leads to the
activation of a constitutively active form of TGF-beta-1 and increased
proliferation of osteoblasts.

.0002
CAMURATI-ENGELMANN DISEASE
TGFB1, ARG218HIS

In affected members of 2 Japanese families with Camurati-Engelmann
disease (131300), Kinoshita et al. (2000) found a 653G-A transition in
the TGFB1 gene resulting in an arg218-to-his (R218H) missense amino acid
substitution.

.0003
CAMURATI-ENGELMANN DISEASE
TGFB1, ARG218CYS

In 2 families of European descent, and 3 Japanese families, with
Camurati-Engelmann disease (131300), Kinoshita et al. (2000) found that
affected individuals had a 652C-T transition in the TGFB1 gene resulting
in an arg218-to-cys (R218C) missense mutation.

Janssens et al. (2000) found this mutation in 3 European families.

Kinoshita et al. (2004) stated that R218C was the most frequent mutation
among the 40 reported families with CED that had been analyzed for
mutation in the TGFB1 gene. The arginine residue at codon 218 is
evolutionarily conserved among species and also affects the dimerization
of the TGFB1 latency-associated peptide (LAP).

McGowan et al. (2003) studied osteoclast formation in vitro from
peripheral blood mononuclear cells obtained from 3 related CED patients
harboring the R218C mutation, in comparison with 1 family-based and
several unrelated controls. Osteoclast formation was enhanced
approximately 5-fold and bone resorption approximately 10-fold in CED
patients, and the increase in osteoclast formation was inhibited by
soluble TGF-beta type II receptor (190182). Total serum TGFB1 levels
were similar in affected and unaffected subjects, but concentrations of
active TGFB1 in conditioned medium of osteoclast cultures was higher in
the 3 CED patients than in the unaffected family member. The authors
concluded that the R218C mutation increases TGFB1 bioactivity and
enhances osteoclast formation in vitro. The activation of osteoclast
activity was consistent with clinical reports that showed biochemical
evidence of increased bone resorption as well as bone formation in CED.

.0004
CAMURATI-ENGELMANN DISEASE
TGFB1, TYR81HIS

In a European family, Janssens et al. (2000) found a tyr81-to-his (Y81H)
substitution in the TGFB1 gene as the cause of Camurati-Engelmann
disease (131300).

.0005
CAMURATI-ENGELMANN DISEASE
TGFB1, CYS223ARG

In affected members of a Japanese family with Camurati-Engelmann disease
(131300), Kinoshita et al. (2004) identified a 667T-C transition in exon
4 of the TGFB1 gene, resulting in a cys223-to-arg (C223R) mutation.

.0006
CAMURATI-ENGELMANN DISEASE
TGFB1, CYS223GLY

In affected members of a Japanese family with Camurati-Engelmann disease
(131300), Kinoshita et al. (2004) identified a 667T-G transition in exon
4 of the TGFB1 gene, resulting in a cys223-to-gly (C223G) mutation.

.0007
CYSTIC FIBROSIS LUNG DISEASE, MODIFIER OF
BREAST CANCER, INVASIVE, SUSCEPTIBILITY TO, INCLUDED
TGFB1, LEU10PRO

Drumm et al. (2005) found that patients with cystic fibrosis (CF;
219700) and homozygosity for the common phe508del mutation (602421.0001)
had an increased risk of severe pulmonary disease (odds ratio = 2.2) if
they were also homozygous for C at nucleotide 29 of the TGFB1 gene,
corresponding to a change in codon 10. The authors referred to this
genotype as codon 10 CC and the SNP as C29T. A change from the more
common base at this position, T, to C results in an amino acid change
from leucine to proline (L10P) (Knowles, 2005).

In a study of 1,019 Canadian pediatric CF patients, Dorfman et al.
(2008) found a significant association between earlier age of first P.
aeruginosa infection and MBL2 (154545) deficiency (onset at 4.4, 7.0,
and 8.0 years for low, intermediate, and high MBL2 groups according to
MBL2 genotype, respectively; p = 0.0003). This effect was amplified in
patients with the high-producing genotypes of TGFB1, including variant C
of codon 10. MBL2 deficiency was also associated with more rapid decline
of pulmonary function, most significantly in those homozygous for the
high-producing TGFB1 genotypes (p = 0.0002). However, although TGFB1
affected the modulation of age of onset by MBL2, there was no
significant direct impact of TFGB1 codon 10 genotypes alone. The
findings provided evidence for a gene-gene interaction in the
pathogenesis of CF lung disease, whereby high TGFB1 production enhances
the modulatory effect of MBL2 on the age of first bacterial infection
and the rate of decline of pulmonary function.

In a study of 472 CF patient/parent trios, Bremer et al. (2008) found
that a 3-SNP haplotype (CTC) composed of the -509 SNP (dbSNP rs1800469)
C allele, the codon 10 SNP (dbSNP rs1982073) T allele, and a 3-prime SNP
(dbSNP rs8179181) C allele was highly associated with increased lung
function in patients grouped by CFTR genotype. Bremer et al. (2008)
concluded that TGFB1 is a modifier of CF lung disease, with a beneficial
effect of certain variants on the pulmonary phenotype.

In studies using data contributed to the Breast Cancer Association
Consortium (BCAC), Cox et al. (2007) found evidence for a significant
dose-dependent association of the proline-encoding allele of the L10P
SNP (dbSNP rs1982073) with increased risk of invasive breast cancer (see
114480) based on analyses of data from 11 studies comprising 12,946
cases and 15,109 controls. Odds ratios of 1.07 and 1.16 were observed
for heterozygotes and rare homozygotes, respectively, compared with
common homozygotes. Cox et al. (2007) noted that the proline variant has
been associated with higher circulating levels of acid-activatable
TGF-beta and increased rates of TGF-beta secretion in in vitro
transfection experiments. The significant association of the proline
variant was confined to individuals with progesterone receptor
(607311)-negative tumors (P = 0.017).

*FIELD* SA
Roberts et al. (1986); Sporn et al. (1986)
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*FIELD* CN
Ada Hamosh - updated: 7/26/2011
Paul J. Converse - updated: 5/6/2011
Patricia A. Hartz - updated: 2/17/2011
Ada Hamosh - updated: 1/4/2011
Paul J. Converse - updated: 8/3/2010
Ada Hamosh - updated: 6/11/2010
Marla J. F. O'Neill - updated: 5/10/2010
Ada Hamosh - updated: 2/18/2010
Marla J. F. O'Neill - updated: 10/1/2009
Marla J. F. O'Neill - updated: 8/20/2009
Ada Hamosh - updated: 7/9/2009
Ada Hamosh - updated: 8/29/2008
Ada Hamosh - updated: 8/12/2008
Cassandra L. Kniffin - updated: 6/2/2008
Ada Hamosh - updated: 4/4/2008
Ada Hamosh - updated: 3/26/2008
Ada Hamosh - updated: 7/31/2007
Marla J. F. O'Neill - updated: 4/12/2007
Anne M. Stumpf - updated: 4/10/2007
Ada Hamosh - updated: 3/13/2007
George E. Tiller - updated: 1/16/2007
Cassandra L. Kniffin - updated: 12/28/2006
Paul J. Converse - updated: 9/13/2006
Patricia A. Hartz - updated: 7/20/2006
Paul J. Converse - updated: 7/5/2006
Cassandra L. Kniffin - updated: 6/8/2006
Victor A. McKusick - updated: 10/17/2005
Cassandra L. Kniffin - updated: 9/7/2005
Marla J. F. O'Neill - updated: 7/28/2005
Patricia A. Hartz - updated: 7/25/2005
Patricia A. Hartz - updated: 7/6/2005
George E. Tiller - updated: 4/25/2005
Patricia A. Hartz - updated: 4/19/2005
Cassandra L. Kniffin - updated: 2/21/2005
Marla J. F. O'Neill - updated: 1/28/2005
Patricia A. Hartz - updated: 11/16/2004
Ada Hamosh - updated: 9/29/2004
John A. Phillips, III - updated: 8/2/2004
Patricia A. Hartz - updated: 6/17/2004
Victor A. McKusick - updated: 5/26/2004
Marla J. F. O'Neill - updated: 5/7/2004
Natalie E. Krasikov - updated: 3/30/2004
Victor A. McKusick - updated: 8/27/2003
Victor A. McKusick - updated: 4/16/2003
Patricia A. Hartz - updated: 4/4/2003
Ada Hamosh - updated: 3/24/2003
Patricia A. Hartz - updated: 3/5/2003
Victor A. McKusick - updated: 2/28/2003
Victor A. McKusick - updated: 2/25/2003
Patricia A. Hartz - updated: 12/16/2002
Victor A. McKusick - updated: 10/1/2002
Jane Kelly - updated: 7/9/2002
Victor A. McKusick - updated: 4/25/2002
Victor A. McKusick - updated: 1/2/2002
Victor A. McKusick - updated: 10/2/2001
John A. Phillips, III - updated: 7/6/2001
Ada Hamosh - updated: 5/2/2001
Victor A. McKusick - updated: 10/25/2000
Victor A. McKusick - updated: 9/1/2000
Victor A. McKusick - updated: 8/28/2000
Victor A. McKusick - updated: 6/1/2000
Victor A. McKusick - updated: 4/20/2000
Ada Hamosh - updated: 10/23/1999
Victor A. McKusick - updated: 2/17/1999
Stylianos E. Antonarakis - updated: 7/14/1998
Victor A. McKusick - updated: 1/15/1998
Victor A. McKusick - updated: 12/3/1997
Michael J. Wright - updated: 9/25/1997

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
terry: 05/24/2012
alopez: 8/8/2011
terry: 7/26/2011
mgross: 5/6/2011
terry: 3/9/2011
carol: 3/3/2011
mgross: 2/18/2011
terry: 2/17/2011
alopez: 1/4/2011
alopez: 8/6/2010
terry: 8/3/2010
alopez: 6/16/2010
terry: 6/11/2010
wwang: 5/13/2010
terry: 5/10/2010
alopez: 2/25/2010
terry: 2/18/2010
wwang: 10/1/2009
wwang: 9/8/2009
terry: 8/20/2009
alopez: 7/16/2009
terry: 7/9/2009
terry: 6/3/2009
alopez: 9/11/2008
terry: 8/29/2008
alopez: 8/25/2008
terry: 8/12/2008
wwang: 6/17/2008
ckniffin: 6/2/2008
alopez: 4/14/2008
terry: 4/4/2008
alopez: 3/28/2008
terry: 3/26/2008
carol: 2/21/2008
mgross: 8/23/2007
terry: 8/7/2007
alopez: 8/3/2007
terry: 7/31/2007
wwang: 6/7/2007
alopez: 6/6/2007
wwang: 4/25/2007
wwang: 4/18/2007
terry: 4/12/2007
alopez: 4/10/2007
alopez: 3/13/2007
wwang: 1/22/2007
terry: 1/16/2007
wwang: 12/28/2006
ckniffin: 12/28/2006
mgross: 9/20/2006
terry: 9/13/2006
mgross: 8/2/2006
mgross: 7/20/2006
mgross: 7/6/2006
terry: 7/5/2006
wwang: 6/23/2006
ckniffin: 6/8/2006
wwang: 5/18/2006
ckniffin: 5/16/2006
alopez: 10/27/2005
alopez: 10/24/2005
terry: 10/17/2005
wwang: 9/30/2005
ckniffin: 9/7/2005
wwang: 8/19/2005
alopez: 8/10/2005
terry: 7/28/2005
mgross: 7/28/2005
terry: 7/25/2005
mgross: 7/8/2005
mgross: 7/7/2005
terry: 7/6/2005
carol: 6/13/2005
tkritzer: 4/25/2005
mgross: 4/20/2005
terry: 4/19/2005
terry: 3/23/2005
wwang: 3/8/2005
tkritzer: 3/7/2005
ckniffin: 3/4/2005
ckniffin: 2/21/2005
terry: 1/28/2005
mgross: 11/16/2004
tkritzer: 10/1/2004
terry: 9/29/2004
alopez: 8/2/2004
mgross: 6/23/2004
carol: 6/17/2004
terry: 6/17/2004
tkritzer: 6/8/2004
terry: 5/26/2004
carol: 5/12/2004
terry: 5/7/2004
carol: 4/29/2004
terry: 3/30/2004
cwells: 11/10/2003
cwells: 8/28/2003
terry: 8/27/2003
carol: 4/18/2003
terry: 4/16/2003
carol: 4/9/2003
carol: 4/4/2003
alopez: 3/24/2003
terry: 3/24/2003
carol: 3/5/2003
alopez: 2/28/2003
alopez: 2/25/2003
terry: 2/25/2003
mgross: 12/17/2002
terry: 12/16/2002
carol: 10/2/2002
tkritzer: 10/2/2002
tkritzer: 10/1/2002
mgross: 7/9/2002
mgross: 4/25/2002
cwells: 3/13/2002
carol: 1/16/2002
mcapotos: 1/8/2002
terry: 1/2/2002
alopez: 11/5/2001
alopez: 10/8/2001
terry: 10/2/2001
alopez: 7/6/2001
alopez: 5/3/2001
terry: 5/2/2001
alopez: 10/31/2000
terry: 10/25/2000
terry: 10/11/2000
mcapotos: 9/8/2000
mcapotos: 9/7/2000
mcapotos: 9/1/2000
mcapotos: 8/31/2000
alopez: 8/28/2000
terry: 8/28/2000
mcapotos: 6/15/2000
mcapotos: 6/14/2000
terry: 6/1/2000
mcapotos: 5/11/2000
mcapotos: 5/9/2000
terry: 4/20/2000
alopez: 10/23/1999
kayiaros: 7/8/1999
mgross: 2/25/1999
mgross: 2/19/1999
terry: 2/17/1999
carol: 7/14/1998
mark: 1/19/1998
mark: 1/16/1998
terry: 1/15/1998
dholmes: 1/12/1998
mark: 12/3/1997
alopez: 11/12/1997
alopez: 11/11/1997
alopez: 11/10/1997
mark: 9/18/1996
mark: 1/23/1996
mark: 1/9/1996
mark: 12/12/1995
terry: 9/13/1995
supermim: 3/16/1992
carol: 3/2/1992
supermim: 5/15/1990
supermim: 3/20/1990
ddp: 10/27/1989

RBCC Red Blood Cell Collection

Full text data of TGFB1