TGFBR1andTGFBR2mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome

Abstract

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder characterized by manifestations in the cardiovascular, skeletal, ocular, and other organ systems. MFS type1 (MFS1) is caused by mutations in the gene encoding fibrillin (FBN1). Recently, the transforming growth factor-beta receptor-2 gene, TGFBR2, has been shown to be associated with a second type of this disorder with typically mild or absent ocular involvement (MFS type 2; MFS2). Several point mutations were found in the highly conserved serine/threonine kinase domain of TGFBR2. Mutations in both TGFBR1 and TGFBR2 are associated with Loeys-Dietz aortic aneurysm syndrome (LDS). We searched for TGFBR1 and TGFBR2 mutations in 41 unrelated patients fulfilling the diagnostic criteria of Ghent nosology or with the tentative diagnosis of Marfan syndrome, in whom mutations in the FBN1 coding region were not identified. In TGFBR1, two mutations and two polymorphisms were detected. In TGFBR2, five mutations and six polymorphisms were identified. Reexamination of patients with a TGFBR1 or TGFBR2 mutation revealed extensive clinical overlap between patients with MFS1, MFS2, and LDS.

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

“…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).…”

“…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). 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).…”

“…(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).…”

“…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.…”

Association of the TGF-β receptor genes with abdominal aortic aneurysm

“…12 Dysregulated TGF-bsignaling by mutations in the receptor genes, TGFBR1 and TGFBR2, causes thoracic aortic aneurysm (TAA) syndromes, including Marfan syndrome type II (OMIM 154705), 13,14 Loeys-Dietz syndrome (OMIM 609192), 14,15 and thoracic aortic aneurysms leading to type A dissections. 16,17 Although these syndromes are clinically distinct, their phenotypes overlap, with TAA and aortic dissections as the common denominator.…”