De novo mutation of the latency‐associated peptide domain of TGFB3 in a patient with overgrowth and Loeys–Dietz syndrome features

Exome sequencing identifies a novel heterozygous TGFB3 mutation in a disorder overlapping with Marfan and Loeys-Dietz syndrome

“…In vitro analyses suggested that decreased TGFbeta signalling resulting from a loss of TGFB3 activity was likely responsible for the clinical phenotype. The TGFB3 mutation we report p.(Arg300Gly) affects the same codon as the p.(Arg300Gln) mutation identified by Matyas et al [8] and the p.(Arg300Trp) mutations identified by Bertoli-Avela et al [9] leading to the assumption that p.Arg300 is a mutational hotspot. Comparison of the clinical findings of all individuals carrying a TGFB3 mutation at position p.Arg300 (see Table 2 as well as supplementary data in [9]) reveals several similarities, especially tall stature with marfanoid habitus -consistent with MFS, and hypertelorism and bifid uvula -consistent with LDS.…”

“…Comparison of the clinical findings of all individuals carrying a TGFB3 mutation at position p.Arg300 (see Table 2 as well as supplementary data in [9]) reveals several similarities, especially tall stature with marfanoid habitus -consistent with MFS, and hypertelorism and bifid uvula -consistent with LDS. Although in the first two papers [7,8] and in our family no evidence for a major cardiovascular involvement associated with TGFB3 mutations was observed, which is in contrast to MFS and LDS (see Table 2 type 4, respectively [10,11]. Thus, although the number of reported patients is small and experimental evidence in the case of TGFB3 is lacking, the short or tall stature seen in patients with TGFB3 mutations may result from opposing effects of mutations on TGF-beta signalling [12].…”

“…Sanger sequencing confirmed the mutation and its segregation with the phenotype. The first two TGFB3 mutations were reported previously in two unrelated individuals with marfanoid features: one individual with growth retardation carried a heterozygous loss-of-function mutation (c.1226G>A; p.Cys409Tyr; Rienhoff et al, 2013), whereas a child with overgrowth carried a mutation in the same codon as the mutation identified in the three affected individuals reported here (c.899G>A; p.Arg300Gln; Matyas et al, 2014). The mutations at codon Arg300 presumably lead to increased TGF-beta signalling, suggesting that the short or tall stature seen in patients with TGFB3 mutations may result from opposing effects of mutations on TGF-beta signalling.…”

“…This bias might possibly be due to the rather young age of the affected patients reported by Matyas, by Rienhoff, and by us. Moreover, different mutations at different positions in the gene might also lead to variable clinical features.As pointed out by Matyas et al[8], mutations affecting the C-terminal end of the LAP domains of TGFB1 and TGFB2 lead to increased TGF-beta signalling in Camurati-Engelmann syndrome and LDS…”

Response to “De novo mutation of the TGFB3 latency‐associated peptide domain in a patient with overgrowth and Loeys–Dietz syndrome features”

“…The correspondence from Matyas et al [2014] is intriguing. The authors have identified a mutation [c. 899G>A,p.Arg300Gln] in the portion of the TGFB3 gene coding for the cleavage recognition site between TGFB3 propeptide or latency-associate peptide (LAP) and the mature TGFB3 ligand.…”