In other species: chicken , turkey , domestic cat , sheep , American mink

Categories: Muscle phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 602307 (gene)

Mendelian trait/disorder: unknown

Disease-related: yes

Cross-species summary: Degenerative muscle disorder, leading to muscle weakness, liberation of myoglobin into the circulation from skeletal muscle, and subsequent wasting and possible contracture.

Species-specific description: This is the canine homologue of human Duchenne muscular dystrophy, which is caused by mutations in the dystrophin gene and is characterized by progressive weakness and muscle wasting that is ultimately fatal. Clinical signs begin at 8-10 weeks of age. Absence of the dystrophin protein causes sarcolemma dysfunction, muscular hypercontraction, and ultimately, muscle fiber degeneration. The mode of inheritance is X-linked recessive. Genetic tests are available. Edited by Meg Sleeper, VMD and Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT

History: The first identified case of canine muscular dystrophy was in a Golden Retriever in 1958 (Shelton et al., 2004).

Inheritance: Carrier females usually do not show clinical signs. However, due to random X inactivation, they can occasionally present with limb weakness and highly elevated serum creatine kinase, or show changes on electromyography or biopsy (Shelton et al., 2004; Kornegay et al., 2011).

Mapping: CFX

Molecular basis: All causative mutations occur within the dystrophin gene, although the molecular basis of the dystrophin mutation may be different between breeds. In the Golden Retriever, there is a point mutation in the consensus splice acceptor site in exon 6 of the dystrophin gene, such that exon 7 is skipped during mRNA processing. The amino acid frame shift causes premature termination of the dystrophin protein (Sharp et al., 1992; Bartlett at al., 1996; Howell et al., 1997).

Clinical features: Affected dogs develop clinical signs at 8 to 10 weeks of age. Signs include a shuffling gait or shortened stride (“bunny hopping”), inability to completely open the jaw, difficulty eating, thickening of the base of the tongue, excessive salivation, abduction of front paws, adduction of stifles and hocks, and prominent wasting of temporal and trunk muscles (Shelton, 2004; Valentine et al., 1992; Kornegay et al., 2011). Other signs include spinal and costal curvature, resulting in a crouched posture (Valentine et al., 1992). Elevated serum creatine kinase concentrations (up to 300 times greater than normal) begins during the first week of life age, and is exacerbated by exercise (Valentine et al., 1992). In breeds where a mutation has not been reported, affected dogs can be tentatively diagnosed by immunohistochemical tests for the presence or absence of dystrophin protein in skeletal muscle biopsy (Shelton and Engvall 2002).

Pathology: Clinical signs are caused by the absence of dystrophin protein. Affected animals initially have sarcolemma dysfunction, which results in an increased intracellular calcium and muscle fiber hypercontraction. These are followed by muscle fiber degeneration and necrosis, with some regeneration (Howell et al., 1997). Eventually, muscle fibrosis, mineralization and fat infiltration occur in both skeletal and cardiac muscle. Lesions in cardiac muscle, which are analogous but can be less severe, are usually in the ventricles, and usually occur after 6 months of age (Howell et al., 1997).

Prevalence: Muscular dystrophy in the Golden Retriever (GRMD) has received most study (Kornegay et al., 2011), but has been identified in several breeds.

Control: Female relatives of affected dogs should be tested to identify carriers. Breeding of affected or carrier animals should be avoided.

Genetic testing: Causative mutations are known in the Golden Retriever, Rottweiler, German Shorthaired Pointer, and Cavalier King Charles Spaniel. A PCR-based test is available to detect the mutation in these breeds.

Breeds: Brittany Spaniel (Dog) (VBO_0200239), Cavalier King Charles Spaniel (Dog) (VBO_0200309), German Shorthaired Pointer (Dog) (VBO_0200583), Golden Retriever (Dog) (VBO_0200610), Grand Basset Griffon Vendeen (Dog) (VBO_0200615), Irish Terrier (Dog) (VBO_0200704), Labrador Retriever (Dog) (VBO_0200800), Miniature Schnauzer (Dog) (VBO_0200896), Pembroke Welsh Corgi (Dog) (VBO_0200995), Rat Terrier (Dog) (VBO_0201125), Rottweiler (Dog) (VBO_0201143), Samoyed (Dog) (VBO_0201174), Weimaraner (Dog) (VBO_0201401).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).