Journal
HUMAN MUTATION
Volume 25, Issue 4, Pages 348-352Publisher
WILEY-BLACKWELL
DOI: 10.1002/humu.20152
Keywords
Marfan syndrome; fibrillin-1; MFS; FBN 1; cbEGF-like domain; bovine; animal model
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Funding
- NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH [T32DE007023] Funding Source: NIH RePORTER
- NIDCR NIH HHS [T32DE007023] Funding Source: Medline
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Marfan Syndrome (MFS) is an autosomal dominant disorder caused by mutations in the fibrillin-1 gene (FBN1). Several calves, all sired by a phenotypically normal bull, were found to exhibit the major clinical and pathological characteristics of human MFS (aortic dissection, joint laxity, tens dislocation), and were recognized as potential models of the human disease. In this study, Fbn1 cDNA from affected animals was sequenced and a heterozygous c.3598 G > A transition was detected in exon 29, which predicted the substitution of an evolutionarily conserved glutamic acid by lysine at position 1200 (p.E1200K). This residue is part of a calcium-binding epidermal growth factor-like (cbEGF-like) module, a domain that is frequently altered in human MFS. Analysis of genomic DNA from the original bull's sperm showed that less than 20 % of the sperm harbored the mutation, consistent with the presence of germline mosaicism. This study validates the use of these animals as models of human MFS. These cows will be valuable for investigations into the molecular pathogenesis of MFS, and may lead to better therapeutic testing and evaluation of human Marfan patients. (c) 2005 Wiley-Liss, Inc.
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