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Dobermans With Genetic Heart Disorder May Be Model for Human Treatments

The Belltower at NC State.

Researchers from North Carolina State University and the University of Arizona have identified a gene associated with a common cause of heart disease in Doberman pinschers. Their findings could lead to new therapies for both dogs and humans.

Dilated cardiomyopathy is a fatal genetic heart disorder common in Doberman pinschers. The disease affects the heart muscle’s ability to contract, leading to congestive heart failure or sudden death in adult dogs. Humans with dilated cardiomyopathy have the same grim prognosis; existing medical therapies may extend lifespans but a total heart transplant is currently the only effective treatment.

“The severity of this disease means that Doberman breeders and owners are very interested in both preventing it within the population and finding life-extending treatments,” says Kate Meurs, associate dean and director of graduate programs at NC State’s College of Veterinary Medicine and lead author of a paper describing the work. “If we could find a cause, perhaps we could develop better treatments that would not only benefit dogs, but extend human lives as well.”

Previously, Meurs had discovered that a mutation in the pyruvate dehydrogenase kinase 4 (PDK4) gene could cause dilated cardiomyopathy in Dobermans; however, that mutation ended up being associated with a relatively small number of cases. When Meurs encountered a family of Doberman pinschers with dilated cardiomyopathy and without the PDK4 variant, she wanted to find the genetic cause of their disease.

Meurs and her colleagues performed whole genome sequencing on the Doberman family and analyzed their cardiac myofibers, or bands of heart muscle, under an electron microscope. The team discovered that another gene, called titin, was the culprit.

“For humans with dilated cardiomyopathy, a titin mutation is the most common cause,” Meurs says. “This gene is responsible for producing one of the largest proteins in both people and dogs, and is involved in enabling skeletal and cardiac muscle to contract. This mutation causes cardiac myofibers to stretch out so that the heart muscle cannot do its job properly.”

While titin’s involvement with dilated cardiomyopathy isn’t a new discovery, finding a mutation in the same gene in Doberman pinschers and humans opens up new avenues for possible treatments.

“We now know that the majority of Doberman and human cases of dilated cardiomyopathy are caused by a mutation in titin, which means that not only can breeders now have a reliable test for their dogs, but also that we can begin interventionary therapies earlier,” Meurs says. “This means we can now truly test the effectiveness of potential life-extending therapies on these animals.

“And this benefits human medicine as well, since you can follow therapies in a Doberman to get information at much shorter timescales.”

The research appears in Human Genetics.

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Note to editors: An abstract follows.

“A Missense Variant in the Titin Gene in Doberman Pinscher Dogs with Familial Dilated Cardiomyopathy and Sudden Cardiac Death”

DOI: 10.1007/s00439-019-01973-2

Authors: Kathryn Meurs, Natasha Olby, Darcy Adin, Oriana Yost, Teresa DeFrancesco, North Carolina State University; Chandra Saripalli, Paola Tonino, Henk Granzier, University of Arizona; Diane Shelton, University of California San Diego; et al
Published: Human Genetics

Abstract:
The dog provides an important large animal model of familial dilated cardiomyopathy for the study of important aspects of this common familial cardiovascular disease. We have previously demonstrated a form of canine dilated cardiomyopathy in the Doberman pinscher breed that is inherited as an autosomal dominant trait and is associated with a splice site variant in the pyruvate dehydrogenase kinase 4 (PDK4) gene, however genetic heterogeneity exists in this species as well and not all affected dogs have the PDK4 variant. Whole genome sequencing of a family of Doberman pinchers with dilated cardiomyopathy and sudden cardiac death without the PDK4 variant was performed. A pathologic missense variant in the titin gene located in an immunoglobulin-like domain in the I-band spanning region of the molecule was identified and was highly associated with disease (p<0.0001). Protein analysis revealed normal levels of titin and reduction in active tension. We demonstrate here the identification of a variant in the titin gene highly associated with disease in this spontaneous canine model of dilated cardiomyopathy. This large animal model of familial dilated cardiomyopathy shares many similarities with the human disease including mode of inheritance, clinical presentation, genetic heterogeneity and a pathologic variant in the titin gene. The dog is an excellent model to improve our understanding of the genotypic phenotypic relationships, penetrance, expression and the pathophysiology of variants in the titin gene.

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