Muscular Dystrophy, Duchenne type

 

Gene: DMD (Dystrophin)

Transmission: X-linked recessive

For an X-chromosome linked recessive genetic disease, a male must have a copy of the mutation in question to be at risk of developing the disease. All affected males transmit the mutation to all females in their progeny.  A female must have two copies of the mutation in question to be at risk of developing the disease. Females with a single copy of the mutation are not at risk of developing the disease, but are carrier animals that can transmit the mutation to on average one-half of their offspring.

Mutations:

Golden Retriever mutation: Substitution (splicing error), DMD gene; c.531-2 A>G, intron6-7

German Shorthaired Pointer mutation: Deletion of entire DMD gene

Cavalier King Charles Spaniel mutation (I): Substitution (splicing error), DMD gene; c.7294+5 G>T

Cavalier King Charles Spaniel mutation (II): Deletion, DMD gene; c.6057_6063 del TCTCAAT, p.(N2021P fs)

Pembroke Welsh Corgi mutation: Insertion, DMD gene; LINE-1 insertion (4.8Kb) into intron13 with inframe STOP

Cocker Spaniel mutation: Deletion, DMD gene; deletion 4 nt exon 65, fs STOP

Tibetan Terrier mutation: Deletion, DMD gene; Large deletion encompassing exon8 to exon29

Labrador Retriever mutation (I): Insertion, DMD gene; Insertion 184 nt between exon19 and exon20 with frameshift, premature STOP

Labrador Retriever mutation (II): 2.2Mb chromosomal inversion involving DMD gene

Labrador Retriever mutation (III): Chromosomal duplication within DMD gene

Japanese Spitz mutation: Inversion of 5.4Mb of X chromosome implicating DMD gene

Norfolk Terrier mutation: Deletion, DMD gene; c.3084 del.G, p.(G1029N fs STOP 30)

Miniature Poodle mutation: Deletion of entire DMD gene

Border Collie mutation: Deletion, DMD gene; c.2841 del.T,

Jack Russell Terrier mutation: Deletion of 368Kb within the DMD gene

Britany Spaniel mutation (I): Insertion, DMD gene; retrogene (RSPYR1) insertion, intron20

Britany Spaniel mutation (II): Substitution, DMD gene; c.8059 C>T, p.(Q2687 STOP)

French Bulldog mutation: Insertion, DMD gene; c.3371_3372 ins.A, p.(F1125 fs)

Labradoodle mutation: Substitution, DMD gene; c.2668 C>T, p.(R890 STOP), exon21

Medical system: Muscular

Breeds: [breeds]

Age of onset of symptoms: Variable, depending on mutation: from 8 weeks after birth to young adulthood.

Muscular dystrophy is a disease characterized by a progressive decline and weakness of the animal’s skeletal muscles.  The DMD gene is a large gene found on the X chromosome that codes for the Dystrophin protein which is involved in muscle contraction.  Spontaneous mutations within the DMD gene can give rise to muscular dystrophy in a number of species including man, the dog and the cat.  The muscular dystrophy is characterized by progressive muscle fiber destruction with some compensatory but inadequate reconstruction, and often leads to the early death of the animal.  As the DMD gene is located on the X chromosome, the muscular dystrophy displays sex linked heredity, whereby male animals that are affected by the disease will have mothers that are carriers for the mutation in question.  Because female carriers are easily identified by their affected male offspring, the mutations within the DMD gene that give rise to muscular dystrophy tend to be self-limiting within isolated pedigrees.  If the mutation within the DMD gene causes severe loss of Dystrophin protein function, the more severe phenotype of Duchenne muscular dystrophy is seen.  If the mutation within the DMD gene cause only partial loss of dystrophin protein function, the milder Beckers muscular dystrophy is seen.  It should be noted that mutations within autosomal genes can also be responsible for different forms of muscular dystrophy.

Muscular dystrophy in the dog was first reported and characterized in the Golden Retriever dog breed in 1992.  Independent mutations within the DMD gene have now been identified in a number of breeds.  Affected puppies can have difficulty nursing, resulting in decreased growth rates.  By 6 to 8 weeks of age, an abnormal gait (bunny hopping) can be evident.  Other signs of the disease include a crouching posture, spinal curvature and excessive drooling.  Affected puppies are often euthanized for humanitarian reasons.  However, symptoms and progression of the disease can be variable, and mildly affected animals can survive for several years.  Because the Dystrophin gene is found on the X-chromosome the disease displays sex-linked heredity between generations: unaffected carrier female bitches will pass the mutation and the disease to on average half of their male offspring, while half of their female offspring will be unaffected carriers.  Since affected males are evident and carrier females easily identified, the disease is self limiting within a breed.

 

References:

OMIA link: [1081-9615]

Donner J, Freyer J, Davison S, et al. (2023) Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs.  PLoS Genet. 19(2):e1010651. [pubmed/36848397]

Hakim CH, Teixeira J, Leach SB, Duan D. (2023) Physiological assessment of muscle, heart, and whole body function in the canine model of Duchenne muscular dystrophy. Methods Mol Biol 2587:67-103.  [pubmed/36401025]

Shelton GD, Minor KM, Friedenberg SG, et al. (2023) Current classification of canine muscular dystrophies and identification of new variants. Genes (Basel) 14(8):1557. [pubmed/37628610]

Gaina G, Popa Gruianu A. (2021) Muscular dystrophy: Experimental animal models and therapeutic approaches (Review). Exp Ther Med 21:610, 2021. [pubmed/33936267]

Schneider SM, Sansom GT, Guo LJ, et.al. (2021) Natural history of histopathologic changes in cardiomyopathy of Golden Retriever Muscular Dystrophy. Front Vet Sci 8:759585. [pubmed/35252412]

Barthélémy I, Calmels N, Weiss RB, et.al. (2020) X-linked muscular dystrophy in a Labrador Retriever strain: phenotypic and molecular characterization. Skelet Muscle 10:23. [pubmed/32767978]

Story BD, Miller ME, Bradbury AM, et al. (2020) Canine models of inherited musculoskeletal and neurodegenerative diseases. Front Vet Sci 7:80. (pubmed/32219101]

Wasala NB, Hakim CH, Chen SJ, et al. (2019) Questions Answered and Unanswered by the First CRISPR Editing Study in a Canine Model of Duchenne Muscular Dystrophy. Hum Gene Ther 30:535-543. [pubmed/30648435]

Kornegay JN. (2017) The golden retriever model of Duchenne muscular dystrophy.  Skelet Muscle 7:9  [pubmed/28526070]

Brinkmeyer-Langford C, Kornegay JN. (2013) Comparative genomics of X-linked muscular dystrophies: The Golden Retriever Model. Curr Genomics 14(5):330-42. [pubmed/24403852]

Kornegay JN, Bogan JR, Bogan DJ, et al. (2012) Canine models of Duchenne muscular dystrophy and their use in therapeutic strategies. Mamm Genome 23(1-2):85-108. Epub 2012 Jan 5. Review. [pubmed/22218699]

Sharp NJ, Kornegay JN, Van Camp SD, et al. (1992) An error in dystrophin mRNA processing in golden retriever muscular dystrophy, an animal homologue of Duchenne muscular dystrophy. Genomics 13(1):115-21. [pubmed/1577476]

 

Contributed by:  Laurie-Maude Huot and Iris-Andrea Garcia-Rosales, Class of 2027, and Jeanne St-Germain and Alice Beillouin, Class of 2028, Faculty of Veterinary Medicine, University of Montreal.  (Translation, DWS)