Dystrophin (DMD) Missense Variant in Cats with Becker-Type Muscular Dystrophy

Abstract

Muscular dystrophy due to dystrophin deficiency in humans is phenotypically divided into a severe Duchenne and milder Becker type. Dystrophin deficiency has also been described in a few animal species, and few DMD gene variants have been identified in animals. Here, we characterize the clinical, histopathological, and molecular genetic aspects of a family of Maine Coon crossbred cats with clinically mild and slowly progressive muscular dystrophy. Two young adult male littermate cats exhibited abnormal gait and muscular hypertrophy with macroglossia. Serum creatine kinase activities were highly increased. Histopathologically, dystrophic skeletal muscle exhibited marked structural changes including atrophic, hypertrophic, and necrotic muscle fibers. Immunohistochemistry showed irregularly reduced expression of dystrophin but the staining of other muscle proteins such as β- and γ-sarcoglycans as well as desmin was also diminished. Whole genome sequencing of one affected cat and genotyping of the littermate found both to be hemizygous mutant at a single DMD missense variant (c.4186C>T). No other protein-changing variants in candidate genes for muscular dystrophy were detected. In addition, one clinically healthy male littermate was hemizygous wildtype, while the queen and one female littermate were clinically healthy, but heterozygous. The predicted amino acid exchange (p.His1396Tyr) resides in a conserved central rod spectrin domain of dystrophin. Various protein modeling programs did not predict major disruption of the dystrophin protein by this substitution, but the altered charge of the region may still affect protein function. This study represents the first genotype-to-phenotype correlation of Becker-type dystrophin deficiency in companion animals.

Precision medicine using whole genome sequencing identifies a novel dystrophin (DMD) variant for X‐linked muscular dystrophy in a cat

“…In 1992, two 5‐month‐old male domestic shorthair littermates with muscle hypertrophy as a prominent clinical feature of the disease were described, 14 followed in 1994 by the first molecular description of a deletion in the DMD promotor in a male cat with similar clinical and histopathologic findings as the previous reports 15 . Recently, a nonsense variant was identified in a family of Maine coon cats 16 and a missense variant in a family of Maine coon crossbred cats 17 . Herein, we report a highly deleterious variant causing loss of function (LoF) and likely underlying dystrophin‐deficient MD in a random bred cat from the United Kingdom.…”

“…15 Recently, a nonsense variant was identified in a family of Maine coon cats 16 and a missense variant in a family of Maine coon crossbred cats. 17 Herein, we report a highly deleterious variant causing loss of function (LoF) and likely underlying dystrophin-deficient MD in a random bred cat from the United Kingdom.…”

“…With the improvement of molecular techniques, such as short-read whole genome sequencing (WGS) and, to some extent, whole exome sequencing (WES), distinguishing among various myopathies is now possible by rapid identification of the underlying variant responsible for causing disease, 23,24 including MD in both dogs and cats. 17,25 Increased availability of next-generation sequencing allows identification of new pathogenic genes and the wide spectrum of clinical phenotypes associated with known defective proteins. The deletion in the muscle promoter of DMD was 1 of the earliest genetic variants discovered in the cat.…”

“…Clinical examination cannot distinguish among various myopathies including the MDs, and further diagnostic testing is necessary including evaluation of muscle biopsy samples by histopathology, histochemistry, immunohistochemistry, and measurement of serum creatine kinase (CK) activity. With the improvement of molecular techniques, such as short‐read whole genome sequencing (WGS) and, to some extent, whole exome sequencing (WES), distinguishing among various myopathies is now possible by rapid identification of the underlying variant responsible for causing disease, 23,24 including MD in both dogs and cats 17,25 …”

“…Cytosine (C) are blue peaks and thymine (T) are red peaks.defined because of the limitations of the techniques of discovery 65. Two additional DMD variants in cats were characterized recently, both in families of Maine coon cats 16,17. A previous report described a nonsense variant in exon 11 of the feline DMD gene, NC_058386.XM_045050794.1): c.1180C>T (p.Arg394*), which was supported by mRNA sequencing and demonstrated the loss of most of the dystrophin protein 16.…”