Mutation of the gene encoding fibrillin-2 results in syndactyly in mice

Fibrillins are large, cysteine-rich glycoproteins that form microfibrils an d play a central role in elastic fibrillogenesis. Fibrillin-1 and fibrillin -2, encoded by FBN1 on chromosome 15q21.1 and FBN2 on chromosome 5q23-q31, are highly similar proteins. The finding of mutations in FBN1 and FBN2 in t he autosomal dominant microfibrillopathies Marfan syndrome (MFS) and congen ital contractural arachnodactyly (CCA), respectively, has highlighted their essential role in the development and homeostasis of elastic fibres, MFS i s characterized by cardiovascular, skeletal and ocular abnormalities, and C CA by long, thin, flexed digits, crumpled ears and mild joint contractures, Although mutations arise throughout FBN1, those clustering within exons 24 -32 are associated with the most severe form of MFS, so-called neonatal MFS , All the mutations described in CCA occur in the 'neonatal region' of FBN2 , Both MFS and CCA are thought to arise via a dominant negative mechanism. The analysis of mouse mutations has demonstrated that fibrillin-1 microfibr ils are mainly engaged in tissue homeostasis rather than elastic matrix ass embly. In the current investigation, we have analysed the classical mouse m utant shaker-with-syndactylism using a positional candidate approach and de monstrated that loss-of-function mutations outside the 'neonatal region' of Fbn2 cause syndactyly in mice, These results suggest that phenotypes disti nct from CCA may result in man as a consequence of mutations outside the 'n eonatal region' of FSN2,