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Am J Med Genet A
2013 Aug 01;161A8:2040-6. doi: 10.1002/ajmg.a.36056.
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A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome.
Rienhoff HY, Yeo CY, Morissette R, Khrebtukova I, Melnick J, Luo S, Leng N, Kim YJ, Schroth G, Westwick J, Vogel H, McDonnell N, Hall JG, Whitman M.
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The transforming growth factor β (TGF-β) family of growth factors are key regulators of mammalian development and their dysregulation is implicated in human disease, notably, heritable vasculopathies including Marfan (MFS, OMIM #154700) and Loeys-Dietz syndromes (LDS, OMIM #609192). We described a syndrome presenting at birth with distal arthrogryposis, hypotonia, bifid uvula, a failure of normal post-natal muscle development but no evidence of vascular disease; some of these features overlap with MFS and LDS. A de novo mutation in TGFB3 was identified by exome sequencing. Several lines of evidence indicate the mutation is hypomorphic suggesting that decreased TGF-β signaling from a loss of TGFB3 activity is likely responsible for the clinical phenotype. This is the first example of a mutation in the coding portion of TGFB3 implicated in a clinical syndrome suggesting TGFB3 is essential for both human palatogenesis and normal muscle growth.
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Figure 1. Pictures of the proband at ages 17 months, 36 months, and 6 years. Evident at age 17 months are the prominent eyes, hypertelorism, tubular nose, and retrognathia. Evident at age 36 months are a normal ear, retrognathia, and less pronounced hypertelorism. At age 6 years the inner canthal distance was within normal limits.
Figure 2. Picture of the proband at age 30 months with V.A. McKusick, M.D. Evident in the proband are the blue sclera, the well-placed and normal ear, tubular nose with metopic ridge, mild hyperterlorism, retrognathia, and hypomalar eminences.
Figure 3. TGFB3C409Y does not activate TGF-β signaling. Constructs containing FLAG-tagged TGFB3WT and TGFB3C409Y were expressed in HEK293T cells and secreted FLAG-tagged proteins were immunoprecipitated under native conditions and normalized to anti-FLAG reactivity. Serial dilutions of these proteins were applied to HEK293T cells transfected with p3TP-Lux (TGF-β reporter) and pRL-CMV (normalizer). Error bars are standard error of the mean (N = 3).
Figure 4. TGFB3C409Y acts as a dominant inhibitor of TGF-β signaling. Indicated amount of synthetic mRNAs were microinjected into Xenopus embryos after fertilization, and embryos harvested at Stage 9 for Western blot analysis. A representative Western blot is shown in A. B–D: Quantitation of densitometric analysis of three independent experiments is shown, measuring phosphorylated SMAD (pSMAD2) activation (pSMAD2/total SMAD2 ratio), pERK activation (pERK/ERK ratio), and total SMAD2, ERK, and cytoplasmic actin levels, respectively, following injection of mRNAs as indicated. Data are presented with error bars representing standard error of the mean. For each experiment, the intensity Western signal was standardized relative to the wild type TGFB/TGFBR2 co-injected condition (lane 3 of panels B–D).
Figure 5. TGFB3C409Y does not disrupt BMP signaling during Xenopus gastrulation. Indicated amounts of synthetic mRNAs for human TGFB3, TGFB3C409Y and Xenopus Noggin were injected into Xenopus laevis embryos to assay perturbations of BMP signaling during gastrulation. The levels of C-terminal phosphorylated SMAD1 (pSMAD1) were examined by immunoblotting. SMAD1 and actin were used as loading controls. Pictured in the lower panel are intact embryos; the BMPR antagonist Noggin disrupts gastrulation while TGFB3C409Y does not.
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