TGFBR3 variation is not a common cause of Marfan-like syndrome and Loeys-Dietz-like syndrome

Krishna K Singh, Joerg Schmidtke, Britta Keyser, Mine Arslan-Kirchner

Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 (FBN1) gene, and mutations in FBN1 are known to be responsible for over 90% of all MFS cases. Locus heterogeneity has also been reported and confirmed, with mutations in the receptor genes TGFBR1 and TGFBR2 identified in association with MFS-related phenotypes. It is now known that dysregulation of TGF-ß signaling is involved in MFS pathogenesis. To test the hypothesis that dysregulation of TGFBR3-associated TGF-ß signaling is implicated in MFS or related phenotype pathogenesis, we selected a cohort of 49 patients, fulfilling or nearly fulfilling the diagnostic criteria for MFS. The patients were known not to carry a mutation in the FBN1 gene (including three 5' upstream alternatively spliced exons), the TGFBR1 and TGFBR2 genes. Mutation screening for the TGFBR3 gene in these patients and in controls led to the identification of a total of ten exonic (one novel), four intronic (one novel) and one 3'UTR variant in the TGFBR3 gene. Our data suggest that variations in TGFBR3 gene appear not to be associated with MFS or related phenotype.