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

Abstract

Marfan syndrome (MFS, OMIM #154700) is a hereditary connective tissue disorder, clinically presenting with cardinal features of skeletal, ocular, and cardiovascular systems. In classical MFS, changes in connective tissue integrity can be explained by defects in fibrillin-1, a major component of extracellular microfibrils. However, some of the clinical manifestations of MFS cannot be explained by mechanical properties alone. Recent studies manipulating mouse Fbn1 have provided new insights into the molecular pathogenesis of MFS. Dysregulation of transforming growth factor beta (TGFb) signaling in lung, mitral valve and aortic tissues has been implicated in mouse models of MFS. TGFBR2 and TGFBR1 mutations were identified in a subset of patients with MFS (MFS2, OMIM #154705) and other MFS-related disorders, including LoeysDietz syndrome (LDS, #OMIM 609192) and familial thoracic aortic aneurysms and dissections (TAAD2, #OMIM 608987). These data indicate that genetic heterogeneity exists in MFS and its related conditions and that regulation of TGFb signaling plays a significant role in these disorders.

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

“…22 In mouse models of Marfan syndrome type I increased TGF-b activity was observed in different organs, including aortic tissue. 23 Similarly, aortic tissues of LoeysDietz syndrome patients showed increased TGF-b signaling activity. 24 Paradoxically, mutations in the receptor genes are primarily located within its intracellular kinase domain, resulting in kinase inactivity.…”

Editor's Choice – Management of Descending Thoracic Aorta Diseases

“…It may be justified by atypical location or character of FBN1 pathogenic variants in some individuals or to locus heterogeneity. 273 MFS has a range of expressions, from mild to severe. The most serious complications are defects of the heart valves and aorta.…”

Marfan syndrome: clinical diagnosis and management

“…4,5 Recently, mutations in the transforming growth factor b-receptor 2 (TGFBR2) gene on chromosome 3 and in the TGFBR1 gene on chromosome 9 were found in some families with apparent Marfan syndrome. 6 -8 These 'Marfan syndrome type 2' (MIM 154705) 9 families seem less likely to have ectopia lentis. TGFBR2 mutations at the R460 codon have also been described in families with the chromosome 3-linked form of familial thoracic ascending aortic aneurysm 10,11 (FTAA3, MIM 608967), and TGFBR1 and 2 mutations are found in Loeys -Dietz syndromes type 1 and 2.…”

“…Although the TGFBR1 and 2 mutations described so far are loss of function mutations, increased TGFb signalling was found in patient tissues and Marfan mouse models, and TGFb blockade by neutralising antibodies or angiotensin II type 1 (AT1) receptor blockers rescues the model phenotypes. 9,12,24 The pathogenetic process must involve a complex disruption of TGFb signalling yet to be elucidated.…”