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522351 
Journal Article 
Bovine model of marfan syndrome results from an amino acid change (c.3598G > A, p.E1200K) in a calcium-binding epidermal growth factor-like domain of fibrillin-1 
Singleton, AC; Mitchell, AL; Byers, PH; Potter, KA; Pace, JM 
2005 
Yes 
Human Mutation
ISSN: 1059-7794
EISSN: 1098-1004 
25 
4 
348-352 
English 
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. 
Marfan syndrome; fibrillin-1; MFS; FBN 1; cbEGF-like domain; bovine; animal model; tgf-beta activation; osteogenesis imperfecta; friesian calves; fbn1; mutation; gene; pathogenesis; recurrence; mosaicism; sequence