Ten novelFBN2mutations in congenital contractural arachnodactyly: Delineation of the molecular pathogenesis and clinical phenotype

Abstract

Congenital contractural arachnodactyly (CCA) is an autosomal dominant condition that shares skeletal features with Marfan syndrome (MFS), but does not have the ocular and cardiovascular complications that characterize MFS. CCA and MFS result from mutations in highly similar genes, FBN2 and FBN1, respectively. All the identified CCA mutations in FBN2 cluster in a limited region similar to where severe MFS mutations cluster in FBN1, specifically between exons 23 and 34. We screened exons 22 through 36 of FBN2 for mutations in 13 patients with classic CCA by single stranded conformational polymorphism analysis (SSCP) and then by direct sequencing. We successfully identified 10 novel mutations in this critical region of FBN2 in these patients, indicating a mutation detection rate of 75% in this limited region. Interestingly, none of these identified FBN2 mutations alter amino acids in the calcium binding consensus sequence in the EGF-like domains, whereas many of the FBN1 mutations alter the consensus sequence. Furthermore, analysis of the clinical data of the CCA patients with characterized FBN2 mutation indicate that CCA patients have aortic root dilatation and the vast majority lack evidence of congenital heart disease. These studies have implications for our understanding of the molecular basis of CCA, along with the diagnosis and genetic counseling of CCA patients.

Comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: Report of 14 novel mutations and review of the literature

“…Importantly, reports on four probands also mention aortic root dilatation, a feature previously thought to be a differentiating finding from Marfan syndrome (MFS; MIM] 154700) [Gupta et al, 2002[Gupta et al, , 2004.…”

“…However, only four groups explicitly stated that they had screened the entire FBN2 gene [Belleh et al, 2000;Maslen et al, 1997;Nishimura et al, 2007;Park et al, 1998], and CCA patients without FBN2 mutations were reported [Gupta et al, 2002]. Moreover, a premature truncating mutation was reported in CCA [Gupta et al, 2002] and could occur in other regions of the gene as well. It therefore remains unclear whether mutations outside the middle region of the FBN2 gene might cause CCA.…”

2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease: Executive Summary

“…42,49 Similarly, patients with congenital contractural arachnodactyly or Beals syndrome due to mutations in FBN2 have had aortic root enlargement without documented progression to dissection. 50,51 There are other genetic syndromes that have multiple reports or documentation of thoracic aortic aneurysms leading to Type A dissections. There are multiple case reports of AoD in patients with autosomal dominant polycystic kidney disease.…”

Microfibrils at Basement Membrane Zones Interact with Perlecan via Fibrillin-1

“…Mutations in fibrillin-1 result in Marfan syn-drome and some related disorders (33), whereas mutations in fibrillin-2 have been shown to lead to congenital contractural arachnodactyly (34,35). The "prototype" of microfibrillar disorders, Marfan syndrome, is primarily characterized by symptoms in the cardiovascular, skeletal, and ocular systems.…”