CLUSTERING OF FBN2 MUTATIONS IN PATIENTS WITH CONGENITAL CONTRACTURALARACHNODACTYLY INDICATES AN IMPORTANT ROLE OF THE DOMAINS ENCODED BY EXONS 24 THROUGH 34 DURING HUMAN-DEVELOPMENT

Congenital contractural arachnodactyly (CCA) is an autosomal dominant condition phenotypically related to Marfan syndrome (MFS), CCA is caus ed by mutations in FBN2, whereas MFS results from mutations in FBN1. F BN2 mRNA extracted from 12 unrelated CCA patient cell strains was scre ened for mutations, and FBN2 mutations were identified in six of these samples. All of the identified FBN2 mutations cluster in a limited re gion of the gene, a region where mutations in FBN1 produce the severe, congenital form of MFS (so-called neonatal MFS). Furthermore, three o f the identified mutations occur in the FBN2 locations exactly corresp onding to FBN1 mutations that have been reported in cases of neonatal MFS, These mutations indicate that this central region of both of the fibrillins plays a critical role in human embryogenesis. The limited r egion of FBN2 that can be mutated to cause CCA may also help to explai n the rarity of CCA compared to MFS, (C) 1998 Wiley-Liss, Inc.