Dilated Cardiomyopathy (ABCC9 related)

 

Gene: ABCC9

Transmission : Autosomal recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease.  Both parents of an affected animal must be carriers of at least one copy of the mutation.  Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutation: Substitution, ABCC9 gene; c.3557 G>A, p.(R1186Q), chr.27.

Medical system: Cardiac

Breeds: English Toy Terrier, Manchester Terrier

Age of onset of symptoms: 2 to 14 months.

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.

A phenotype of sudden death and dilated cardiomyopathy is described for the Manchester Terrier.  The acute form of the disease involves sudden death in an otherwise healthy animal, usually by 6 months of age but before 2 years of age. A pathology exam shows a heart that is macroscopically normal, while histology reveals acute multifocal myocardial degeneration and necrosis.  In the chronic form, dilated cardiomyopathy is evident on clinical exam and there may be an association with cryptorchidism.  Histology of the heart now reveals myocardial degeneration fibrosis, inflammation and there can be mineralization of the tissues.  Molecular studies revealed a homozygous mutation in the AVCC9 gene, which codes for a cardiac ATP sensitive potassium channel on cardiomyocytes.  DNA testing surveys for the mutation showed a carrier frequency of 8% in Manchester terriers, and of 9% in the English Toy Terrier, a closely related breed.  DNA tests will now enable breeders to identify carrier animals, and through selective breeding, eliminate this disease and eventually this mutation 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]

ABCC9 gene, OMIA link: [2710-9615]

 

References:

OMIA link: [2710-9615]

Furrow E, Tate N, Minor K, et al. (2023) An ABCC9 missense variant is associated with sudden cardiac death and dilated cardiomyopathy in juvenile dogs. Genes (Basel) 14(5):988. [pm/37239348]

Wess G. (2022) Screening for dilated cardiomyopathy in dogs. Journal of Veterinary Cardiology: The Official Journal of the European Society of Veterinary Cardiology, 40:51‑68.  [pm/34732313]

Legge CH, López A, Hanna P, et al. (2013) Histological characterization of dilated cardiomyopathy in the juvenile toy Manchester terrier. Vet Pathol 50:1043-52.  [pm/23456967]

 

Contributed by:  Anthony Turcotte and Jonathan Hotte, Class of 2028, Faculty of Veterinary Medicine, University of Montreal. (Translation DWS).