Mutation screening of complete fibrillin-1 coding sequence: report of five new mutations, including two in 8-cysteine domains

Abstract

Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder characterized by cardiovascular, ocular and skeletal manifestations. Previously, mutations in the fibrillin-1 gene on chromosome 15 (FBN1) have been reported to cause MFS. We have now screened 44 probands with MFS or related phenotypes for alterations in the entire fibrillin coding sequence (9.3 kb) by single strand conformation analysis. We report four unique mutations in the fibrillin gene of unrelated MFS patients. One is a 17 bp deletion and three are missense mutations, two of which involve 8-cysteine motifs. Another missense mutation was found in two unrelated individuals with annuloaortic ectasia but was also present in unaffected relatives and controls from various ethnic backgrounds. By using allele-specific oligonucleotide hybridization, we screened 65 unrelated MFS patients, 29 patients with related phenotypes and 84 control individuals for these mutations as well as for a previously reported mutation and two polymorphisms. Our results suggest that most MFS families carry unique mutations and that the fibrillin genotype is not the sole determinant of the connective tissue phenotype.

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

“…This variability could be explained, in part, by the different techniques used, but the most significant influencing factor is likely to be sample bias. The frequencies are quite different between patients fulfilling the Ghent criteria and those not fulfilling them (Biggin et al 2004;Halliday et al 2002;Loeys et al 2001;Rommel et al 2002Rommel et al , 2005Tynan et al 1993).…”

“…More than 600 FBN1 mutations are registered in the UMD-FBN1 database for MFS and its associated disorders (http:// www.umd.be:2030/) . The mutation detection rate of FBN1 in MFS varies among studies, ranging from 9% to 91% (Katzke et al 2002;Loeys et al 2004;Tynan et al 1993). This variability could be explained, in part, by the different techniques used, but the most significant influencing factor is likely to be sample bias.…”

Quantitative differences in biosynthesis and extracellular deposition of fibrillin in cultured fibroblasts distinguish five groups of Marfan syndrome patients and suggest distinct pathogenetic mechanisms.

“…Subsequently, genetic linkage was established between the Marfan syndrome and the fibrillin gene (FBNI) on chromosome 15 by using intragenic markers (7). Several unique and independent missense, nonsense, and deletion mutations in FBNJ have been reported, which make a strong argument for the primary involvement of this large gene in the causation of MFS (8)(9)(10)(11)(12)(13)(14). The basis for considerable intra-and interfamilial phenotypic variability remains unknown.…”

“…These include nine fibroblast strains with missense mutations (20) and four with various other mutations as described recently (11,13,14).…”

Marfan Syndrome-causing Mutations in Fibrillin-1 Result in Gross Morphological Alterations and Highlight the Structural Importance of the Second Hybrid Domain

“…The remaining mutations, G880S (UMD data base file number 601), C862R (UMD data base file number 27) and C908R (UMD data base file number 463), occur within the second hybrid domain encoded by exons 21 and 22. C862R was a sporadic mutation causing classical MFS with skeletal, ocular, and cardiovascular complications (34). G880S was reported as a sporadic mutation causing the typical skeletal and cardiovascular manifestations of classical Marfan syndrome (35).…”