Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects

Abstract

TGF-b-receptor 2 (TGFBR2) gene defects have been recently associated with Marfan syndrome (MFS) with prominent cardio-skeletal phenotype in patients with negative fibrillin-1 (FBN1) gene screening. Four mutations have been identified to date in five unrelated families. We screened TGFBR2 gene by direct automated sequencing in two adult patients diagnosed with MFS according to Ghent criteria, and in one girl clinically suspected as affected on the basis of a major cardiovascular criterion and skeletal involvement, all proven not to carry mutations in the exon -intron boundaries of FBN1 gene. We identified two novel and one known TGFBR2 gene mutations in the three unrelated probands. The D446N was identified in a 4-year-old girl with de novo disease characterized by severe cardiovascular disease and skeletal involvement. The M425V and R460H mutations were identified in two familial, autosomal dominant MFSs, both characterized by major cardio-skeletal signs and absence of major ocular signs. The mutation R460H has been recently reported in a family with thoracic aortic aneurysms and dissection. The three mutations are absent in 192 controls and affect evolutionarily conserved residues of the serine/ threonine kinase domain (exon 5). Our data support the recently reported association between TGFBR2 gene and MFS without major ocular signs (MFS2). The number of genotyped cases however is too low to confirm that major ocular signs are characteristically absent in MFS2. Accordingly, all patients proven or suspected to be affected by MFS with negative FBN1 gene screening could benefit from rapid investigation of the TGFBR2 gene.

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

“…(Singh et al 2006). However, it should be noted that arterial tortuosity, a cardinal feature of LDS, was not systematically evaluated in any of the four studies (Disabella et al 2006;Matyas et al 2006;Sakai et al 2006;Singh et al 2006). Moreover, two research groups were unable to identify TGFBR2 mutations in 29 MFS patients (FBN1 was normal in 24 and unknown in five) (Ki et al 2005) and seven patients (FBN1 was normal) with MFS compatible with the Ghent criteria (Loeys et al 2005).…”

“…Following the first report of TGFBR2 mutations in MFS (Mizuguchi et al 2004), LDS, TAAD2, SGS, and FS were recognized as TGFBR mutation-related disorders. Although the original MFS2 patients with TGFBR2 mutations (Mizuguchi et al 2004) could not be reasonably re-examined for the presence of LDS features such as bifid uvula, hypertelorism, craniosynostosis, and arterial tortuosity, at least three reports have since described TGFBR1 or TGFBR2 mutations in classic MFS patients in whom LDS had been ruled out (Disabella et al 2006;Matyas et al 2006;Singh et al 2006). (Singh et al 2006).…”

“…At least six TGFBR2 mutations (R356P, N384S, R460H, R460C, S449F, and R537C) and two TGFBR1 mutations (S241L and R487Q) were recognized in two or three conditions (i.e., R460H found in MFS, LDS, and TAAD) (Ades et al 2006;Disabella et al 2006;Ki et al 2005;Loeys et al 2006;Matyas et al 2006;Mizuguchi et al 2004;Pannu et al 2005a;Sakai et al 2006;Singh et al 2006) (Fig. 1, Table 2), implying that TGFBR mutations may cause various clinical consequences or that appropriate diagnosis is rather difficult for these disorders.…”

Marfan Syndrome—An Orthodontic Perspective

“…6 The protein synthesized by this gene transmits signals from the cell surface to the nucleus, thereby affecting cell division and growth. The clinical presentation of type II Marfan syndrome resembles that of classic Marfan syndrome, with the exception that the ocular system usually is not involved.…”

Evaluation of resequencing on number of tag SNPs of 13 atherosclerosis-related genes in Thai population

“…TGFB2 (TGF-b 2) and TGFB3 (TGF-b 3) show significant mRNA expression differences in atherogenic animal models (Tabibiazar et al 2005;Wang et al 2003). TGFBR2 (TGF-b type II receptor) defects have been recently associated with Marfan syndrome (MFS) with a prominent cardioskeletal phenotype (Disabella et al 2006;Matyas et al 2006;Mizuguchi et al 2004).…”