Widespread severe myodegeneration in a compound heterozygote female dog with dystrophin deficiency

Abstract

The University of Missouri (MU) has established a colony of dystrophin-deficient dogs with a mixed breed background to mirror the variable pathologic effects of dystrophinopathies between persons of a given kindred to further the understanding of the genetic and molecular basis of the variable phenotype; thus to facilitate discovery of an effective therapeutic strategy. Herein we report the phenotype and genotype of a normal-appearing 10-month-old colony female that died suddenly. At necropsy examination, there were reduced skeletal and laryngeal muscle volume and mild dilatation of the oesophagus. Microscopic findings consisted of extensive degeneration and regeneration of the axial skeletal, tongue, oesophageal, and laryngeal muscles that were characterized by considerable central nucleation, individual fibre mineralization and interstitial fibrosis. The myocardial findings were limited to infiltration of adipose cells in the interstitium. The female dog was a compound heterozygote with one X chromosome carrying a point mutation in intron 6 of the dystrophin gene and the other X chromosome carrying a repetitive element insertion in intron 13 of the dystrophin gene. Although the direct cause of death was uncertain, it might likely be due to sudden cardiac death as has been seen in Duchenne muscular dystrophy patients. This case demonstrated dystrophinopathy in female dogs that have no ameliorating normal X chromosome.

Keywords: Duchenne muscular dystrophy; canine; compound heterozygote; dystrophin.

FIGURE 1

Representative photomicrographs of different muscles of the mixed breed female dog. A representative area for each combination of histopathological changes is encircled. (A) Heart: adipose cells interstitial infiltration and focal area of coarsely branched cardiomyocytes. (B) Oesophageal muscle: multifocal patches of muscle fibrs in cross section have severely diminished diameters with frequent centralized nuclei and nuclear rowing. Mineralization is frequent in such areas. Rare basophilic regenerating fibres are seen. (C) Skeletal muscle of the tongue: similar lesions are found. (D) Skeletal muscle from the front leg: similar pattern of muscular degeneration applies with focal areas of fibre atrophy, central nuclei, slender blue fibres and nuclear rowing. Patches of muscle have also undergone complete coagulative necrosis. There is loss of striations and fibre fragmentation. (E) Skeletal muscle from the rear leg: similar lesions described in the front leg are found. Haematoxylin and eosin stain

FIGURE 2

Representative Masson trichrome staining photomicrograph of the skeletal muscle from the leg of the mixed breed female dog. (A) There are marked variability in myofibre size and endomysial fibrosis (arrows). (B) Comparative normal image of mason trichome in an unaffected young dog

FIGURE 3

Immunolabelling of dystrophin in axial skeletal muscles of a normal dog (A) and the mixed breed female dog with muscular dystrophy (B). (A) The sarcolemma of a normal dog is labelled immunohistochemically for expression of dystrophin (arrows). (B) The sarcolemmal expression of dystrophin is absent

FIGURE 4

PCR/gel electrophoresis of this study case genotype which exhibits the golden retriever muscular dystrophy (GRMD) and Pembroke Welsh Corgis (WCMD) mutations (GW)