Muscular Dystrophy (Discovered in the Golden Retriever)

Also known as Golden Retriever Muscular Dystrophy (GRMD), because this is the breed in which this disorder was first documented. 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. Edited by Meg Sleeper, VMD and Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT.
All known canine DMD variants that cause Duchenne or Becker like muscular dystrophy are listed in this entry.
This phene includes references to studies involving genetically modified organisms (GMO).

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).

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 (omia.variant:366), 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).
As reported by Kornegay et al. (2012), a causal "nonsense mutation in exon 58" (omia.variant:957) was reported in Rottweilers by Winand et al. (1994).
In two affected German short-haired pointers, Schatzberg et al. (1999) discovered a "deletion encompassing the entire dystrophin [DMD] gene" (omia.variant:680). VanBelzen et al. (2017) provided a detailed characterisation of this deletion.
In the Cavalier King Charles Spaniel, Walmsley et al. (2010) reported "a missense mutation in the 5′ donor splice site of exon 50 that results in deletion of exon 50 in mRNA transcripts and a predicted premature truncation of the translated protein" (omia.variant:367).
In Corgis, Smith et al. (2011) reported "a long interspersed repetitive element-1 (LINE-1) insertion in intron 13, which introduced a new exon containing an in-frame stop codon" as another causal mutation (omia.variant:708).
As well as reviewing past discoveries, Kornegay et al. (2012) reported that they had "identified three additional DMD gene mutations in the Cocker spaniel (deletion of four nucleotides in exon 65, with a reading frame shift predicting a premature stop codon at the site of the deletion, omia.variant:536), Tibetan terrier (a large deletion of exons 8-29, omia.variant:681), and Labrador retriever (184 nucleotide [pseudoexon] insertion between exon 19 and exon 20, which results in a premature stop codon at the next codon downstream of the insertion, omia.variant:729) (Larsen CA et al, unpublished). The Labrador retriever mutation presumably corresponds to one in an earlier [abstract] report (Smith et al 2007)".
Atencia-Fernandez et al. (2015) reported the first causal inversion in a family of Japanese Spitz dogs: "an inversion of a 5.4-Mb fragment of the X chromosome, with one break point (BP1) in the DMD gene . . . and a second break point (BP2) in a gene farther toward the centromere, the RPGR gene" (omia.variant:750).
Jenkins and Forman (2015) reported a 1bp deletion in exon 22 (chr CFAX: 27,606,021; CanFam3); c.3084delG; p.Gly1029AspfsX30 (GenBank:NM001003343, omia.variant:542) in a Norfolk Terrier.
Nghiem et al. (2016) reported "a 7 base pair deletion in DMD exon 42 (c.6051-6057delTCTCAAT mRNA) (omia.variant:562) , predicting a frameshift in gene transcription and truncation of dystrophin protein translation" as the likely causal variant in a "dystrophin-deficient Cavalier King Charles Spaniel".
Sánchez et al. (2018) reported "a >5 Mb deletion on the X chromosome, encompassing the entire DMD gene" (omia.variant:989) as being a likely causal variant in three affected Miniature Poodles.
Mata López et al. (2018) reported a "single nucleotide deletion in canine DMD exon 20, position 27,626,466 (c.2841delT mRNA, omia.variant:1235), resulting in a stop codon six nucleotides downstream" as being causal in a male Border Collie dog.
Schrader et al. (2018) reported "a novel dystrophin mutation in exon 21 [omia.variant:1236] in a line of [affected] Australian Labradoodles".
Barthélémy et al. (2020) reported "a 2.2-Mb inversion disrupting the DMD gene within intron 20 and involving the TMEM47 gene (omia.variant:1234) "as being causal of this disorder in a colony of Labrador Retrievers, whose disorder phenotype is very similar to that in Golden Retrievers.
Brunetti et al. (2020) "identified a ~368kb deletion spanning 19 exons of the canine dystrophin (DMD) gene (omia.variant:1249). This pathogenic loss-of-function variant most likely explains the observed disease phenotype [in a "9-month old male Jack Russell Terrier"]".
Shelton et al. (2022) showed that "the mild form of [muscular dystrophy] MD seen previously in a line of Labrador retrievers" (Vieira et al., 2015, Neuromuscul Disord 25:363-70) is due to "an approximately 400kb tandem genomic DNA duplication including exons 2-7 of the DMD gene (omia.variant:1492) that was inserted into intron 7 of the wild type gene. Skeletal muscle cDNA from 2 cases contained DMD transcripts as expected from an in-frame properly-spliced exon 2-7 tandem insertion".
Shelton et al. (2023) "report the causative mutations for novel forms of X-linked muscular dystrophy in Brittany spaniels and in a French bulldog [omia.variant:1614-1616]." Clinical signs for the two Brittany spaniels were previously reported (Stevens et al. 2022).
Van Poucke et al. (2024) "report the diagnosis and follow-up of mild dystrophin-deficient MD in a 5-month-old male Border Collie, associated with a novel DMD variant.  ...  Inspection of the Sashimi plots of the RNA-seq data from the affected muscle biopsy led to the discovery of a 162-bp L1 pseudoexon in DMD intron 63 [omia.variant:1714], introducing a frameshift and a premature stop codon (NM_001003343.1: c.9271_9272insN[162] p.(Ala3091fs*21))."
Schwarz et al. (2024) "characterize the clinical, histopathological and molecular genetic aspects of two male Entlebucher Mountain Dogs with clinical signs of muscular dystrophy. ... Whole genome sequencing of one affected dog identified an intragenic 8.6 kb duplication in the X-chromosomal DMD gene, c.7528-4048_7645 + 4450dup [omia.variant:1744]. ... The duplication includes exon 52 of DMD and is predicted to lead to a frameshift and truncation of 30% of the wild-type open reading frame. Genotyping of the whole family confirmed the presence of the mutant allele in both affected dogs and the unaffected dam."
Mcleay et al. (2025) report a "~17 kb deletion that encompasses exon 5 of DMD" (omia.variant:1858) as likely causal variant for a canine dystrophinopathy in Shibu Inu littermates. "This same exon 5 deletion has been identified in human dystrophin-deficient muscular dystrophy patients. "This same exon 5 deletion has been identified in human dystrophin-deficient muscular dystrophy patients."

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).

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).

The first identified case of canine muscular dystrophy was in a Golden Retriever in 1958 (Shelton et al., 2004). The first causative mutation for this disorder in dogs, reported by Sharp et al., (1992, Genomics), was the result of cloning and sequencing a very likely comparative candidate gene (based on the same disorder in humans), namely the DMD gene.

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