HGNC Approved Gene Symbol: TGFB2
Cytogenetic location: 1q41 Genomic coordinates (GRCh38) : 1:218,345,336-218,444,619 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q41 | Loeys-Dietz syndrome 4 | 614816 | Autosomal dominant | 3 |
Marquardt et al. (1987) determined the complete amino acid sequence of the TGFB2 gene product. They found that TGFB2 consists of 2 disulfide-linked, identical subunits, each with 112 amino acids. Marquardt et al. (1987) determined that the TGFB2 protein shares 71.4% sequence homology with TGFB1 (190180).
De Martin et al. (1987) and Madisen et al. (1988) isolated the cDNA for human TGFB2, which de Martin et al. (1987) termed glioblastoma-derived T cell suppressor factor (G-TsF). The cDNA predicts that TGFB2 is synthesized as a 442-amino acid polypeptide precursor from which a mature 112-amino acid protein is derived by proteolytic cleavage.
Hanks et al. (1988) determined the complete amino acid sequence of BSC-1 cell growth inhibitor from African green monkey, which was determined to be identical to that of human TGFB2.
By Southern blot analysis of somatic cell hybrid lines and, for the human locus, also by in situ chromosomal hybridization, Barton et al. (1988) mapped TGFB2 to 1q41 in the human and to chromosome 1 in the mouse, most likely in the known conserved syntenic region. Dickinson et al. (1990) also assigned the mouse Tgfb2 gene to chromosome 1. Nishimura et al. (1993) identified 4 RFLPs and SSCPs (single strand conformation polymorphisms) for TGFB2 in humans and gorillas. Using these, they localized the gene within a framework map of distal 1q and showed close linkage to homeobox gene HLX1 (142995); maximum lod score of 14.49 at theta = 0.031.
Proliferative vitreoretinopathy (193235) is characterized by the development of epi- and subretinal fibrocellular membranes containing modified retinal pigment epithelial (RPE) cells among others. Priglinger et al. (2003) found that tissue transglutaminase (190196) was present and functionally active in proliferative vitreoretinopathy membranes. The amount and activity of tissue transglutaminase appeared to be related to the differentiation state of the RPE cells and their stimulation by TGFB2, a growth factor known to be increased in the vitreous of proliferative vitreoretinopathy.
Saika et al. (2007) determined the effects of Smad7 (602932) gene transfer in the prevention of fibrogenic responses by the retinal pigment epithelium, a major cause of proliferative vitreoretinopathy after retinal detachment in mice. In a retinal detachment-induced proliferative vitreoretinopathy in a mouse model, Smad7 gene transfer inhibited TGFB2/Smad signaling in ARPE19 cells and expression of collagen type I and TGFB1 but had no effect on their basal levels. In vivo Smad7 overexpression resulted in suppression of Smad2/3 signals and of the fibrogenic response to epithelial-mesenchymal transition by the retinal pigment epithelium. Saika et al. (2007) concluded that Smad7 gene transfer suppressed fibrogenic responses to TGFB2 by retinal pigment epithelial cells in vitro and in vivo.
TGFB2 is present at elevated levels in the aqueous humor of patients with primary open angle glaucoma (POAG; 137760). Studies have shown that TGFB2 influences cultured trabecular meshwork cells. Gottanka et al. (2004) found that TGFB2 reduced outflow facility when perfused into cultured human anterior segments. Furthermore, TGFB2 affected the extracellular matrix of the trabecular meshwork in a manner that was consistent with the observed reduction in outflow facility. Although the distribution of accumulated fibrillar material was different in these perfused eyes than that in POAG, the difference could have been due to variation in biomechanical environment for trabecular meshwork cells in cultured anterior segments compared with the living eye. Overall, the results supported the hypothesis that elevated TGFB2 levels in the aqueous humor played a role in the pathogenesis of the ocular hypertension in POAG.
Wordinger et al. (2007) studied the effects of altered bone morphogenetic protein signaling on intraocular pressure in POAG. They found that human trabecular meshwork synthesized and secreted BMP4 (112262) as well as expressed the BMP receptor subtypes BMPR1 (see 601299) and BMPR2 (600799). TM cells responded to exogenous BMP4 by phosphorylating SMAD signaling proteins (see 601595). Cultured human TM cells treated with TGFB2 significantly increased fibronectin (FN; 135600) levels, and BMP4 blocked this FN induction. There was significant elevation of mRNA and protein levels of the BMP antagonist Gremlin (GREM1; 603054) in glaucomatous TM cells. In addition, Gremlin was present in human aqueous humor. Gremlin blocked the negative effect of BMP4 on TGFB2 induction of FN. Addition of recombinant Gremlin to the medium of ex vivo perfusion-cultured human eye anterior segments caused the glaucoma phenotype of elevated IOP. Wordinger et al. (2007) concluded that these results were consistent with the hypothesis that, in POAG, elevated expression of Gremlin by TM cells inhibited BMP4 antagonism of TGFB2 and led to increased extracellular matrix deposition and elevated IOP.
Zhang et al. (2019) identified the TGFB signaling pathway as a key upstream regulator of the age-dependent loss of dermal fat and decrease in adipogenesis and cathelidicin production in response to infection in human and mouse skin. TGFB2 and to a lesser extent TGFB1 suppressed the capacity of dermal fibroblasts to differentiate into adipocytes by decreasing the expression of proadipogenic genes, and promoted the loss of antimicrobial activity by increasing the expression of profibrotic and proinflammatory genes. Inhibition of TGFB receptor restored adipogenic and antimicrobial function of dermal fibroblasts in adult mice as well as in cultured primary human dermal fibroblasts.
In 2 unrelated probands with an autosomal dominant aortic aneurysm phenotype that shared features with Loeys-Dietz syndrome (see 609192) and Marfan syndrome (154700), and who also had developmental delay, Lindsay et al. (2012) identified 2 unique heterozygous de novo chromosomal microdeletions at 1q41 by SNP array analysis. Both of these microdeletions overlapped the 'obvious' candidate gene TGFB2. Lindsay et al. (2012) analyzed the TGFB2 gene in 86 individuals with aneurysm who did not have mutations in FBN1 (134797), TGFBR1 (190181), or TGFBR2 (190182) and identified 6 different mutations in 6 probands (see, e.g., 190220.0001 and 190220.0002).
In 2 unrelated families with autosomal dominant thoracic aortic aneurysm, aortic dissection, intracranial aneurysm, and subarachnoid hemorrhage (Loeys-Dietz syndrome type 4; 614816), who were negative for mutation in genes known to be involved in aortic aneurysm syndromes, Boileau et al. (2012) identified heterozygosity for a frameshift and a nonsense mutation in the TGFB2 gene (190220.0003 and 190220.0004) that segregated with disease in each family. Analysis of TGFB2 in 276 additional individuals with thoracic aortic disease, including 62 French probands and 74 French sporadic cases, as well as 214 US probands from families with 2 or more members with thoracic disease, revealed a nonsense and a frameshift mutation in 2 of the French familial cases, respectively.
Sanford et al. (1997) generated Tgfb2 knockout mice. Tgfb2-null mice exhibited perinatal mortality and a wide range of developmental defects including congenital heart defects, skeletal defects (e.g., craniofacial defects such as retrognathia, dysmorphic calvaria, and cleft palate, limb laxity, and spina bifida occulta), eye and inner ear defects, and urogenital defects. The Tgfb2-null phenotype did not overlap with the autoimmune-like inflammatory disease phenotype seen in Tgfb1-null mice.
Lindsay et al. (2012) generated mice haploinsufficient for Tgfb2 and observed dilation of the aortic annulus and root by 8 months of age; the dimensions of the more distal ascending aorta were normal. Protein blot analysis of lysates derived from proximal ascending aortic segments of Tgfb2 +/- mice showed increased phosphorylation of Smad2 (601366), Smad3 (603109), and Erk1/2 (see 600997). Mice with both a mutant Marfan syndrome allele (Fbn1 C1039G) and Tgfb2 haploinsufficiency showed increased TGF-beta signaling and phenotypic worsening in association with normalization of TGF-beta-2 expression and high expression of TGF-beta-1 (190180) compared to wildtype. Lindsay et al. (2012) suggested that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-beta-mediated vasculopathies.
In 4 affected members of a 3-generation family segregating autosomal dominant syndromic thoracic aortic aneurysm (LDS4; 614816), Lindsay et al. (2012) identified heterozygosity for a 1097C-A transversion in exon 7 of the TGFB2 gene, resulting in a pro366-to-his (P366H) substitution at a highly conserved residue in the TGF-beta-2 cytokine domain. The mutation was not found in unaffected family members or in data from the 1000 Genomes Project or in more than 10,000 exomes in the National Heart, Lung, and Blood Institute Exome Variant Server.
In a father and daughter with syndromic thoracic aortic aneurysm (LDS4; 614816), Lindsay et al. (2012) identified heterozygosity for a 15-bp deletion (294_308delCTACGCCAAGGAGGT) in exon 1 of the TGFB2 gene, resulting in in-frame deletion of 5 amino acids (ala100_tyr104del) within the fastener motif. The mutation was not found in data from the 1000 Genomes Project or in more than 10,000 exomes in the National Heart, Lung, and Blood Institute Exome Variant Server.
In affected members of a large 4-generation US family with syndromic thoracic aortic aneurysm (LDS4; 614816), Boileau et al. (2012) identified heterozygosity for a 5-bp deletion (1021_1025delTACAA) in exon 6 of the TGFB2 gene, causing a frameshift resulting in a premature termination codon. TGFB2 expression was similar in smooth muscle cells and dermal fibroblasts from a patient and control cells, but immunoblot analysis of the TGF-beta-2 proprotein in cellular lysates from these cells showed lower amounts of TGF-beta-2 proprotein in mutant cells compared to wildtype with no evidence of a truncated protein, suggesting rapid degradation of the expressed mutant protein.
In affected members of a large 5-generation French family with syndromic thoracic aortic aneurysm (LDS4; 614816), Boileau et al. (2012) identified heterozygosity for a 687C-A transversion in exon 4 of the TGFB2 gene that resulted in a cys229-to-ter (C229X) substitution. The mutation segregated completely with disease in the family and was not present in more than 10,000 chromosomes in the Exome Variant Server.
In 3 affected members of a 4-generation Spanish family with autosomal dominant thoracic aortic aneurysm (LDS4; 614816), Gago-Diaz et al. (2014) identified a C-to-T transition at nucleotide 1042 of the TGFB2 gene (c.1042C-T, NM_001135599.2), which resulted in an arginine-to-cystine substitution at codon 348 (R348C). Affected members had minor connective tissue disease signs such as joint laxity, scoliosis, flat feet, dolichocephaly, and high palate. One affected member had a bicuspid aortic valve. Two unaffected individuals, ages 14 and 44 years, were found to carry the mutation, suggesting possible later development or incomplete penetrance, respectively. The variant was not detected in the Exome Variant Server, HGMD, or in the Locus Specific Database list, and was not present in the ExAC database (March 2018).
Barton, D. E., Foellmer, B. E., Du, J., Tamm, J., Derynck, R., Francke, U. Chromosomal mapping of genes for transforming growth factors beta-2 and beta-3 in man and mouse: dispersion of TGF-beta gene family. Oncogene Res. 3: 323-331, 1988. [PubMed: 3226728]
Boileau, C., Guo, D.-C., Hanna, N., Regalado, E. S., Detaint, D., Gong, L., Varret, M., Prakash, S. K., Li, A. H., d'Indy, H., Braverman, A. C., Grandchamp, B., and 15 others. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nature Genet. 44: 916-921, 2012. [PubMed: 22772371] [Full Text: https://doi.org/10.1038/ng.2348]
de Martin, R., Haendler, B., Hofer-Warbinek, R., Gaugitisch, H., Wrann, M., Schusener, H., Seifert, J. M., Bodmer, S., Fontana, A., Hofer, E. Complementary DNA for human glioblastoma-derived T cell suppressor factor, a novel member of the transforming growth factor-beta gene family. EMBO J. 6: 3673-3677, 1987. [PubMed: 3322813] [Full Text: https://doi.org/10.1002/j.1460-2075.1987.tb02700.x]
Dickinson, M. E., Kobrin, M. S., Silan, C. M., Kingsley, D. M., Justice, M. J., Miller, D. A., Ceci, J. D., Lock, L. F., Lee, A., Buchberg, A. M., Siracusa, L. D., Lyons, K. M., Derynck, R., Hogan, B. L. M., Copeland, N. G., Jenkins, N. A. Chromosomal localization of seven members of the murine TGF-beta superfamily suggests close linkage to several morphogenetic mutant loci. Genomics 6: 505-520, 1990. [PubMed: 1970330] [Full Text: https://doi.org/10.1016/0888-7543(90)90480-i]
Gago-Diaz, M., Blanco-Verea, A., Teixido-Tura, G., Valenzuela, I., Del Campo, M., Borregan, M., Sobrino, B., Amigo, J., Garcia-Dorado, D., Evangelista, A., Carracedo, A., Brion, M. Whole exome sequencing for the identification of a new mutation in TGFB2 involved in a familial case of non-syndromic aortic disease. Clin. Chim. Acta 437: 88-92, 2014. [PubMed: 25046559] [Full Text: https://doi.org/10.1016/j.cca.2014.07.016]
Gottanka, J., Chan, D., Eichhorn, M., Lutjen-Drecoll, E., Ethier, C. R. Effects of TGF-beta-2 in perfused human eyes. Invest. Ophthal. Vis. Sci. 45: 153-158, 2004. [PubMed: 14691167] [Full Text: https://doi.org/10.1167/iovs.03-0796]
Hanks, S. K., Armour, R., Baldwin, J. H., Maldonado, F., Spiess, J., Holley, W. Amino acid sequence of the BSC-1 cell growth inhibitor (polyergin) deduced from the nucleotide sequence of the cDNA. Proc. Nat. Acad. Sci. 85: 79-82, 1988. [PubMed: 3277172] [Full Text: https://doi.org/10.1073/pnas.85.1.79]
Lindsay, M. E., Schepers, D., Bolar, N. A., Doyle, J. J. Gallo, E., Fert-Bober, J., Kempers, M. J. E., Fishman, E. K., Chen, Y., Myers, L., Bjeda, D., Oswald, G., and 15 others. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nature Genet. 44: 922-927, 2012. [PubMed: 22772368] [Full Text: https://doi.org/10.1038/ng.2349]
Madisen, L., Webb, N. R., Rose, T. M., Marquardt, H., Ikeda, T., Twardzik, D., Seyedin, S., Purchio, A. F. Transforming growth factor-beta-2: cDNA cloning and sequence analysis. DNA 7: 1-8, 1988. [PubMed: 3162414] [Full Text: https://doi.org/10.1089/dna.1988.7.1]
Marquardt, H., Lioubin, M. N., Ikeda, T. Complete amino acid sequence of human transforming growth factor type beta-2. J. Biol. Chem. 262: 12127-12131, 1987. [PubMed: 3476488]
Nishimura, D. Y., Purchio, A. F., Murray, J. C. Linkage localization of TGFB2 and the human homeobox gene HLX1 to chromosome 1q. Genomics 15: 357-364, 1993. [PubMed: 8095486] [Full Text: https://doi.org/10.1006/geno.1993.1068]
Priglinger, S. G., May, C. A., Neubauer, A. S., Alge, C. S., Schoenfeld, C.-L., Kampik, A., Welge-Lussen, U. Tissue transglutaminase as a modifying enzyme of the extracellular matrix in PVR membranes. Invest. Ophthal. Vis. Sci. 44: 355-364, 2003. [PubMed: 12506096] [Full Text: https://doi.org/10.1167/iovs.02-0224]
Saika, S., Yamanaka, O., Nishikawa-Ishida, I., Kitano, A., Flanders, K. C., Okada, Y., Ohnishi, Y., Nakajima, Y., Ikeda, K. Effect of Smad7 gene overexpression on transforming growth factor beta-induced retinal pigment fibrosis in a proliferative vitreoretinopathy mouse model. Arch. Ophthal. 125: 647-654, 2007. [PubMed: 17502504] [Full Text: https://doi.org/10.1001/archopht.125.5.647]
Sanford, L. P., Ormsby, I., Gittenberger-de Groot, A. C., Sariola, H., Friedman, R., Boivin, G. P., Cardell, E. L., Doetschman, T. TGF-beta-2 knockout mice have multiple developmental defects that are non-overlapping with other TGF-beta knockout phenotypes. Development 124: 2659-2670, 1997. [PubMed: 9217007] [Full Text: https://doi.org/10.1242/dev.124.13.2659]
Wordinger, R. J., Fleenor, D. L., Hellberg, P. E., Pang, I.-H., Tovar, T. O., Zode, G. S., Fuller, J. A., Clark, A. F. Effects of TGF-beta-2, BMP-4, and gremlin in the trabecular meshwork: implications for glaucoma. Invest. Ophthal. Vis. Sci. 48: 1191-1200, 2007. [PubMed: 17325163] [Full Text: https://doi.org/10.1167/iovs.06-0296]
Zhang, L., Chen, S. X., Guerrero-Juarez, C. F., Li, F., Tong, Y., Liang, Y., Liggins, M., Chen, X., Chen, H., Li, M., Hata, T., Zheng, Y., Plikus, M. V., Gallo, R. L. Age-related loss of innate immune antimicrobial function of dermal fat is mediated by transforming growth factor beta. Immunity 50: 121-136, 2019. [PubMed: 30594464] [Full Text: https://doi.org/10.1016/j.immuni.2018.11.003]