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

Abstract

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, lens 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.3598G > 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.

Identification of the Bovine Arachnomelia Mutation by Massively Parallel Sequencing Implicates Sulfite Oxidase (SUOX) in Bone Development

“…Her paternal copy of the critical 7.19 Mb interval carries the arachnomelia mutation, while her maternal copy is still in its ancestral wild-type state. The BTA 5 haplotypes were confirmed by microsatellite genotyping of available samples from Beautician, Leon, Amaranto, Elegant, Collection, and Valbella [5].…”

“…Initially, it was assumed that the pathogenesis of bovine arachnomelia resembles that of human Marfan syndrome, which is caused by mutations in the FBN1 gene [1]. However, the identification of other cattle with a mutation in the FBN1 gene established that arachnomelia is phenotypically distinct from Marfan syndrome [5]. Arachnomelia affected calves lack some typical Marfan features such as joint laxity and aortic root dilation [3].…”

Arachnomelia in Brown Swiss cattle maps to chromosome 5

“…However, recent clinical findings recorded in arachnomelia-affected calves differ from the typical picture of human Marfan patients (Testoni and Gentile 2004). Moreover, a different phenotype, more closely resembling human Marfan syndrome, has recently been described in cattle harboring a disease-causing mutation in the bovine FBN1 gene (Singleton et al 2005).…”

Thoracic endovascular stent grafting inhibits aortic growth: an experimental study

“…It would be highly interesting to evaluate the influence of endovascular stenting as described in our current study on aortic growth in a previously described bovine model of Marfan syndrome [25,26]. If inhibition of growth should be observed due to fibrosis of the aortic wall, the concept of prophylactic endovascular therapy as a treatment for early stages of aortic dilatation in connective tissue disease could be reassessed.…”