An animal model of the marfan syndrome

Abstract

A congenital syndrome of long, thin limbs, severe joint and tendon laxity, microspherophakia, ectopia lentis, heart murmurs and aortic dilatation was identified in 7 calves. All affected calves were sired by a single phenotypically normal bull suspected of germline mosaicism for a new mutation resulting in this disease. One of the calves subsequently died with ruptured aorta at age 16 months. Histopathologic and electron microscopic studies of the aortic media of affected calves demonstrated disorganized elastin and narrowed elastic lamina separated by widened spaces. This bovine disease provides a unique animal model of the human Marfan syndrome. A herd of cattle with this disease is being developed for further studies.

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

“…Given this ratio, the bull was suspected of germline mosaicism for a mutation [Besser et al, 1990], and the percentage of affected calves suggested that about 10% of the sperm harbored the mutation. To confirm that the bull was mosaic in the germline, DNA was isolated from frozen sperm and amplified by PCR, and the product was then digested with EcoRI, which cuts only the normal allele (see Materials and Methods).…”

“…Several anatomical and biochemical studies showed that these calves share features of human MFS [Besser et al, 1990;Pessier and Potter, 1996;Potter and Besser, 1994;Potter et al, 1993], but the genetic basis of the disease was, until now, unknown. Now that the mutation is identified and known to be typical of human mutations, these large mammals are verified as reasonable experimental models of human disease.…”

“…In contrast to these mouse models, a naturally occurring bovine model of disease, first described by Besser et al [1990], was shown to manifest all the major signs of human MFS ( Fig. 1) and appeared to result from heterozygosity for a mutation, which at that time was undetermined.…”

Veterinary Dysmorphology

“…The affected animals have long, thin limbs, laxity of the joints, lens abnormalities, aortic dilation, etc. (Besser et al, 1990); 2) recessive autosomal mutations, such as the one that causes anotia, cleft palate and bifid tongue in St. Bernard dogs (Villagómez & Alonso, 1998); 3) recessive X-linked mutations, such as the one that occurs in the ectodysplasin A1 and A2 gene isoforms (EDA-A1 and EDA-A2) and causes X-linked hypohidrotic ectodermal dysplasia in dogs (Casal et al 2005). Affected individuals have imperfect teeth, oligodontia and cutaneous areas with no piloglandular units, as shown in Figure 4 (Moura & Cirio, 2004); 4) deletions of Y chromosome genes, such as the one of the sex-determining region Y gene (SRY), which determines sex reversal in horses, i.e., it leaves individuals with an male XY karyotype with a female phenotype and ovaries (Raudsepp et al, 2010); 5) chromosomal aberrations, such as trysomy of chromosome 30 in horses, which makes them smaller than normal, with a and hundredth day of pregnancy.…”

Marfan syndrome in the third Millennium

“…55 The similarities between the human and the bovine diseases suggest that similar metabolic defects could be responsible. To date, although reduced immunostained fibrillin in cultured aortic smooth muscle cells in this limousine calf, 56 no mutation in the corresponding bovine FBN1 gene or in another gene was yet identified in this model.…”