Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes

Abstract

Marfan syndrome (MFS), one of the most common genetic disorders of connective tissue, is characterized by skeletal, cardiovascular and ocular abnormalities. The incidence of the disease is about 1 in 20,000, with life expectancy severely reduced because of cardiovascular complications. As the underlying defect is unknown, MFS diagnosis is based solely on clinical criteria. Certain phenotypic features of MFS are also shared by other conditions, which may be genetically distinct entities although part of a clinical continuum. Immunohistochemical studies have implicated fibrillin, a major component of elastin-associated microfibrils, in MFS aetiology. Genetic linkage analysis with random probes has independently localized the MFS locus to chromosome 15. Here we report that these two experimental approaches converge with the cloning and mapping of the fibrillin gene to chromosome 15q15-21, and with the establishment of linkage to MFS. We also isolated a second fibrillin gene and mapped it to chromosome 5q23-31. We linked this novel gene to a condition, congenital contractural arachnodactyly, that shares some of the features of MFS. Thus, the cosegregation of two related genes with two related syndromes implies that fibrillin mutations are likely to be responsible for different MFS phenotypes.

New insights into elastic fiber assembly

“…A total of three fibrillins (fib-1, -2, and -3) have been identified (Sakai et al, 1986;Lee et al, 1991a;Corson et al, 2004), although the gene for fibrillin-3 has been disrupted in rodents due to chromosome rearrangement (Corson et al, 2004). The primary structure of fibrillin is dominated by calcium binding epidermal growth factor (EGF)-like domains that develop a rod-like structure in the presence of calcium (Downing et al, 1996).…”

Cell adhesion and integrin binding to recombinant human fibrillin‐1

“…So far two members of this family, fibrillin-1 [3][4][5][6] and fibrillin-2 [4,7], have been described as products of different genes. These proteins share a common organization of domains consisting mostly of calcium-binding EGF-like repeats and novel motifs containing 8 cysteines, which are also found in the family of TGF-13 binding proteins [3,5,8].…”

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

“…Marfan syndrome Molecular diagnosis of MFS became possible after mutations had been identified in the FBN1 gene (Dietz et al 1991;Lee et al 1991). FBN1 is a 230 kb gene, containing 65 exons, which encodes the structural protein fibrillin-1 ).…”