In other species: dog , pig

Categories: Muscle phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 300376 (trait) , 300377 (gene)

Links to MONDO diseases:

• MONDO:0010311: Becker muscular dystrophy

Mendelian trait/disorder: yes

Mode of inheritance: X-linked recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2023

Cross-species summary: Variants in the DMD gene may give rise to phenotypes with different severity. True null alleles cause the more severe Duchenne muscular dystrophy (OMIA:001081), while alleles with partial remaining protein function give rise to the milder Becker muscular dystrophy.

Species-specific name: X-linked muscular dystrophy

Molecular basis: Hilton et al. (2023) studied a small family of Maine Coon crossbred cats, in which two male siblings had a mild form of muscular dytrophy. By comparing whole genome sequencing data from an affected cat to the genomes of 74 control cats, the authors identified a private missense variant in the functional candidate gene DMD as most likely causative variant. "... This DMD missense variant in exon 30 constitutes a G>A exchange at position 27,988,938 on the short arm of the X-chromosome, XM_045050787.1:c.4186C>T [OMIAvariantID:1531]. This variant is predicted to result in a histidine-to-tyrosine substitution in the DMD protein, XP_044906722.1:p.(His1396Tyr). The predicted amino acid substitution lies within the spectrin 10 domain of the protein, which is conserved among mammals ..." Two male affected cats carried the mutant allele in hemizygous state and the authors demonstrated the expected co-segregation of the mutant allele in a small family. The mutant allele was absent from "277 control Maine Coon cats and 320 additional control cats of diverse other breeds." Immunohistochemistry of skeletal muscle biopsies demonstrated irregular and partially deficient expression of dystrophin together with diminished antibody reactivity of β- and γ-sarcoglycan. The immunohistochemistry was thus consistent with a partial loss of dystrophin function (Hilton et al. 2023).
Muto et al. (2024): "Whole-genome sequencing identified a novel and unique hemizygous nonsense genetic variant, c.8333G > A in dystrophin (DMD), potentially causing a premature termination codon (p.Trp2778Ter) [OMIAvariantID:1667]. Based on a combination of clinical and histological findings and the presence of the DMD nonsense genetic variant, this case was considered FXMD which showed mild clinical signs and long-term survival, even though immunohistochemical characterization was lacking."
Yokoyama et al. (2024) conducted whole genome sequencing on an affected Kinkalow cat and identified a likely causal nonsense variant in DMD (felCat9: ChrX:27350268G>A, OMIAvariantID:1684). The variant was not present in the parents of this animal and was not detected in 354 cats screened for the variant;  the authors concluded that this was a de novo mutation.

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: "A 2.5-year-old castrated male domestic cat (index case, cat #1) and its male litter-mate (cat #2) were presented to the Tierärztliche Klinik für Kleintiere, Neu-Anspach, Germany, because of clumsy gait, difficulty jumping and grooming, and protrusion of the tongue tip. These cats lived in- and outdoors in a suburban neighbor-hood without any major physical impediments according to their owners. ... Physical examinations of the two affected male littermates revealed a normal body condition score but marked generalized muscular hypertrophy, particularly of the neck and upper limbs, as well as macroglossia and a more forceful breathing pattern. There was no muscle cramping and dimpling, making a congenital myopathy unlikely. Imaging of both the body cavities and heart of cat #1 and cat #2 did not reveal any abnormalities besides the systemic skeletal muscular hypertrophy. There were no cardiac murmurs auscultated, pulse rate and quality appeared normal, and echocardiogram parameters were in normal reference intervals, thus providing no clinical evidence of a cardiomyopathy. Furthermore, there was neither clinical nor radiographic evidence of megaesophagus in either of the affected cats." (Hilton et al. 2023). Serum creatine kinase (CK) activities of the affected cats were massively elevated. Aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were moderately elevated in the affected cats (Hilton et al. 2023).
Yokoyama et al. (2024): "The affected cat was a 10-month-old castrated male Kinkalow (a mix of American Curl and Munchkin breeds) diagnosed with dystrophin-deficient MD ... . The cat was referred ... to investigate persistent increases in serum liver enzyme activities. ... At presentation, the affected cat showed no clinical signs, with normal gait and postural reactions, and physical examination was normal, including the tongue. ... An abdominal ultrasound examination determined that the diaphragm was thickened ... . ... a muscle biopsy was performed because of suspicion of MD. Two hours after waking from anesthesia, the cat underwent cardiopulmonary arrest with suspected rhabdomyolysis and died."

Pathology: "... Transverse and longitudinal sections of gastrocnemius muscle obtained from cat #1 showed structural changes consistent with a dystrophic myopathy: Bimodal pathological fiber size variations, comprising multiple enlarged and atrophic myocytes, as well as muscle fiber necrosis, were present. Furthermore, chronic diffuse myofibrosis, nuclear internalization, and interstitial lymphocytic infiltration were seen. No ragged-red myofibers, cones, rods, cores, and targets were seen, but there were myocytes with increased fibrils and clumping of the myotubular apparatus. Very mild hypomyelination was noted in endomysial nerve fibers. Enzyme histochemistry and myosin heavy chain immunohistochemistry revealed normal type 1 and 2 fiber distribution. Mild increases in subsarcolemmal and interfibrillar lipid droplets were found in a few muscle fibers. Positive acid phosphatase activity highlighted necrotizing myofibers. Together, these histopathological features were consistent with a dystrophic myopathy ..." (Hilton et al. 2023)
Yokoyama et al. (2024): "Histopathology of the rectus abdominis muscle and diaphragm biopsy specimens showed marked variability in myofiber size and myofibers undergoing degeneration and necrosis with calcium deposits, fibrosis, and macrophage infiltration ... . Histopathology of the liver showed no abnormalities. Immunohistochemistry showed that dystrophin staining was not detectable in the affected cat ... ."

Breeds: Domestic Shorthair, Kinkalow (Cat) (VBO_0100142), Maine Coon (Cat) (VBO_0100154).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: