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Heterozygous TGFBR2 mutations in Marfan syndrome


Marfan syndrome is an extracellular matrix disorder with cardinal manifestations in the eye, skeleton and cardiovascular systems associated with defects in the gene encoding fibrillin (FBN1) at 15q21.1 (ref. 1). A second type of the disorder (Marfan syndrome type 2; OMIM 154705) is associated with a second locus, MFS2, at 3p25–p24.2 in a large French family (family MS1)2. Identification of a 3p24.1 chromosomal breakpoint disrupting the gene encoding TGF-β receptor 2 (TGFBR2) in a Japanese individual with Marfan syndrome led us to consider TGFBR2 as the gene underlying association with Marfan syndrome at the MSF2 locus. The mutation 1524G→A in TGFBR2 (causing the synonymous amino acid substitution Q508Q) resulted in abnormal splicing and segregated with MFS2 in family MS1. We identified three other missense mutations in four unrelated probands, which led to loss of function of TGF-β signaling activity on extracellular matrix formation. These results show that heterozygous mutations in TGFBR2, a putative tumor-suppressor gene implicated in several malignancies, are also associated with inherited connective-tissue disorders.

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Figure 1: TGFBR2 was isolated from the 3p24.1 breakpoint of a Japanese individual with complex chromosomal abnormalities.
Figure 2: Haplotype analysis of a large French family (family MS1) and a mutation causing abnormal splicing.
Figure 3: Genomic structure of TGFBR2 and mutations found in families with Marfan syndrome.
Figure 4: Impairment of TGF-β signaling activity by TGFBR2 missense mutations in individuals with Marfan syndrome.

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We thank the affected individuals and their families for their participation; Y. Noguchi, K. Miyazaki and N. Yanai for technical assistance; T. Imamura and K. Miyazono for cell lines Mv1Lu and DR-26 and reporter constructs p3TP-Lux and p15P751-Luc (with permission from J. Massague); and S. Tuffery-Giraud and C. Béroud for technical and scientific discussions. This study was supported in part by CREST, Japan Science and Technology Agency, and by Université René Descartes-Paris V, Ministère de l'Education Nationale, de l'Enseignement Supérieur, de la Recherche et de l'Insertion Professionnelle, Fondation de France, and Faculté de Médecine Necker.

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Correspondence to Catherine Boileau or Naomichi Matsumoto.

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Supplementary Table 1

Clinical data for members of the MSI family. (PDF 5 kb)

Supplementary Methods (PDF 493 kb)

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Mizuguchi, T., Collod-Beroud, G., Akiyama, T. et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 36, 855–860 (2004).

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