Dilated Cardiomyopathy risk factor, PDK4

Dilated Cardiomyopathy risk factor, PDK4

Gene: PDK4

Transmission: Autosomal dominant, with incomplete penetration (complex genetics)

For an autosomal dominant genetic disease, an animal must have at least one copy of the mutation in question to be at risk of developing the disease. Animals with two copies of the mutation generally have more severe symptoms and an earlier onset of the disease than animals with just one copy of the mutation. One or both of the parents of an animal with the mutation has one or two copies of the mutation. Animals that have one or two copies of the mutation can pass the mutation on to future generations.

Mutation: Deletion, PDK4 gene; c.1115+1_1115+16 del. intron10-11

Medical system: Cardiac

Breeds: Akita, Alaskan Malamute, American Bulldog, American Cocker Spaniel, American Foxhound, American Hairless Terrier, American Staffordshire Terrier/Amstaff, Australian Shepherd, Beagle, Bedlington Terrier, Belgian Malinois, Biewer Terrier, Bloodhound, Bluetick Coonhound, Border Collie, Boston Terrier, Boxer, Bull Terrier, Catahoula Leopard Dog, Chesapeake Bay Retriever, Chihuahua, Chinese Crested, Dachshund Miniature Longhair/Shorthair, Danish Swedish Farmdog, Doberman Pinscher, English Bulldog, Fox Terrier - Wire, French Bulldog, German Shepherd, Golden Retriever, Great Dane, Great Pyrenees, Irish Terrier, Kromfohrlander, Labrador Retriever, Lacy Dog, Lakeland Terrier, Maltese Terrier, Manchester Terrier, Mastiff (Old English), Mi-ki, Miniature American Shepherd, Neapolitan Mastiff, Nova Scotia Duck Tolling, Old English Sheepdog, Olde English Bulldogge, Parson Russell Terrier, Pembroke Welsh Corgi, Plott Hound, Pomeranian, Poodle - Miniature (Dwarf), Pug, Redbone Coonhound, Rhodesian Ridgeback, Rottweiler, Russell Terrier, Schnauzer - Miniature, Shih Tzu, Siberian Husky, Silky Terrier, Toy Australian Shepherd, Treeing Walker Coonhound, Welsh Terrier, Yorkshire Terrier

Age of onset of symptoms: Variable, between 1 and 8 years

Dilated cardiomyopathy (DCM) is a common primary heart disease seen in several breeds of dog with both genetic and environmental causes. The genetics of DCM is complex, with several genes and mutations contributing to a juvenile or adult-onset disease that can display either dominant or recessive heredity. As a result of the genetic mutation, heart muscle cells function inefficiently which in turn results in compensatory ventricle dilatation, inefficient contraction, and heart arrhythmias. Clinical signs of DCM include sudden death due to the arrhythmias or prolonged congestive heart failure with exercise intolerance, fatigue, coughing, difficulty breathing, weight loss, fluid accumulation in the abdomen, and fainting. In terms of comparison, mutations in over 60 genes have been associated with a high risk of dilated cardiomyopathy in humans.

The incidence of CMD in the Dobermann is particularly high, at 58% (2017 study), with sudden death seen in 23-30% of these cases. In the Dobermann, mutations in two genes, PDK4 and TTN, which respectively code for a metabolic enzyme and a structural protein in heart muscle, are now identified as risk factors for CMD. These mutations are also seen in many other breeds of dog, at varying frequencies. DNA tests are now available to help breeders identify carrier animals with the goal of eliminating the disease and eventually the mutations from their animals.

Mutations in additional genes that can be risk factors or be responsible for DCM in the dog:

PLN gene, OMIA link: [2195-9615]

PDK4 gene, OMIA link: [0162-9615]

TTN gene, OMIA link: [0162-9615]

RBM20 gene, OMIA link: [2365-9615]

LMNA gene, OMIA link: [2796-9615]

References:

OMIA link: [0162-9615]

Aherne M. (2023) Cardiac disease and screening in breeding dogs. Vet Clin North Am Small Anim Pract 53(5):985-1012. [pubmed/37353418]

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]

Freid KJ, Freeman LM, Rush JE, et al. (2021) Retrospective study of dilated cardiomyopathy in dogs. J Vet Intern Med 35:58-67 [pubmed/33345431]

Shen L, Estrada AH, Meurs KM, et al. (2021) A review of the underlying genetics and emerging therapies for canine cardiomyopathies. J Vet Cardiol, S1760-2734(21)00057-6. [pubmed/34147413]

Meurs KM, Friedenberg SG, Kolb J, et al. (2019) A missense variant in the Titin gene in Doberman Pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death. Hum Genet 138, no. 5: 515-24. [pubmed/30715562]

Dutton E, López-Alvarez J. (2018) An update on canine cardiomyopathies – is it all in the genes? J Small Anim Pract 59(8),455-464. [pubmed/29665072]

Wess G, Domenech O, Dukes-McEwan J et al. (2017) European Society of Veterinary Cardiology screening guidelines for dilated cardiomyopathy in Doberman Pinschers. J Vet Cardiol. 19(5):405-415. [pubmed/28965673]

Owczarek-Lipska M, Mausberg TB, Stephenson H, et al. (2013) A 16-bp deletion in the canine PDK4 gene is not associated with dilated cardiomyopathy in a European cohort of Doberman Pinschers. Anim Genet. 44(2):239. [pubmed/22834541]

Meurs KM, Sahmers S, Keene BW, et al. (2012) A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomhyopathy in the Doberman pinscher. Hum Genet 131:1319-1325. [pubmed/22447147]

Mausberg TB, Wess G, Simak J, et al. (2011) A locus on chromosome 5 is associated with dilated cardiomhyopathy in Doberman Pinschers. PLOS One 6(5):e20042. [pubmed/21625443]