A Nonsense Variant in the DMD Gene Causes X-Linked Muscular Dystrophy in the Maine Coon Cat

Abstract

(1) Feline dystrophin-deficient muscular dystrophy (ddMD) is a fatal disease characterized by progressive weakness and degeneration of skeletal muscles and is caused by variants in the DMD gene. To date, only two feline causal variants have been identified. This study reports two cases of male Maine coon siblings that presented with muscular hypertrophy, growth retardation, weight loss, and vomiting. (2) Both cats were clinically examined and histopathology and immunofluorescent staining of the affected muscle was performed. DMD mRNA was sequenced to identify putative causal variants. (3) Both cats showed a significant increase in serum creatine kinase activity. Electromyography and histopathological examination of the muscle samples revealed abnormalities consistent with a dystrophic phenotype. Immunohistochemical testing revealed the absence of dystrophin, confirming the diagnosis of dystrophin-deficient muscular dystrophy. mRNA sequencing revealed a nonsense variant in exon 11 of the feline DMD gene, NC_058386.1 (XM_045050794.1): c.1180C>T (p.(Arg394*)), which results in the loss of the majority of the dystrophin protein. Perfect X-linked segregation of the variant was established in the pedigree. (4) ddMD was described for the first time in the Maine coon and the c.1180C>T variant was confirmed as the causal variant.

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

“…Duchenne-type muscular dystrophy, characterized by an early severe disease course and complete dystrophin deficiency caused by DMD null variants, has been previously reported in different breeds of domestic dogs (OMIA #001081-9615) [ 5 , 6 , 46 , 47 , 48 , 49 , 50 ], domestic shorthair as well as Maine Coon cats (OMIA #001081-9685) [ 2 , 3 , 4 , 8 , 9 , 11 , 41 , 51 ], pigs [ 16 , 17 , 19 , 20 ], mice [ 25 , 26 ], rats [ 28 ], and rabbits [ 29 ]. In contrast, Becker-type muscular dystrophy has been rarely reported in domestic animals, e.g., in dogs [ 36 , 37 , 38 ] and pigs (OMIA #001888-9823) [ 18 , 23 ].…”

“…The other littermates appeared more like regular domestic shorthair cats. Interestingly, a DMD nonsense variant causing Duchenne-type muscular dystrophy in a Maine Coon family was just reported [ 51 ].…”

“…Consistent with an amino acid substitution in dystrophin, which is not predicted to drastically change the protein structure and stability, immunohistochemistry for dystrophin protein was CRM+. All previously reported cats with dystrophin deficiency were CRM- including the recently reported two Maine Coon cats with Duchenne muscular dystrophy [ 51 ]. Accurate quantification would have been helpful but could not be performed because no samples were available.…”

“…Furthermore, previously studied dystrophin-deficient cats also exhibited reduced complex proteins [ 12 ]. All previously reported cats were classified as having Duchenne-type muscular dystrophy, including the recently described dystrophic Maine Coon cat [ 51 ]. Likewise, human patients with Duchenne-type as well as Becker-type muscular dystrophy have varying degrees of reduced muscle dystrophin-associated complex proteins [ 54 , 55 ].…”

Dystrophin (DMD) missense variant in cats with Becker type muscular dystrophy

“…Consistent with an amino acid substitution in dystrophin, which is not predicted to drastically change the protein structure and stability, immunohistochemistry for dystrophin protein was CRM+. All previously reported cats with dystrophin deficiency were CRMincluding the recently reported two Maine Coon cats with Duchenne muscular dystrophy [51]. Accurate quantification would have been helpful but could not be performed because no samples were available.…”