Genetic analysis of dilated cardiomyopathy in the great dane

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2009-05-15

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Abstract

The domestic dog, Canis familiaris, with over 450 naturally-occurring hereditary diseases, serves as a valuable model organism for study of the genetics underlying many human hereditary diseases. Approximately half of the diseases that afflict the dog are clinically very similar to various human hereditary diseases. Several cardiac diseases are in this category. Our laboratory is interested in cardiac diseases because they are common causes of death in the human and are also a widespread problem in many breeds of dog. The specific focus of my work is on understanding the genetics of dilated cardiomyopathy (DCM). DCM is a disease characterized by enlargement of the left ventricle leading to an inability of the heart to pump sufficient blood to the body. It is one of the most common cardiac diseases in the dog and has a high mortality. The Great Dane is the second most commonly affected breed. It is seen in many families of Great Danes, and this suggests that DCM has a genetic component. The mode of inheritance of DCM in the Great Dane is currently unknown, although studies have reported both autosomal recessive and autosomal dominant transmission. Many different genes cause DCM, indicating the complexity of the disease. These typically produce proteins that are involved in the sarcomere or cytoskeletal components, leading to problems with contraction or cardiac cell integrity. In order to identify causative or susceptibility genes for DCM in the Great Dane, a whole-genome linkage screen was conducted in a family of Great Danes. One candidate gene, gamma-sarcoglycan (SGCG), was identified through linkage and sequenced in affected and unaffected dogs. Sequencing data revealed no mutations in the coding regions of SGCG, most likely excluding it as a candidate gene for DCM. Continued evaluation of this gene and others, both in sequence content and additional properties such as epigenetic effects, protein structure, and interaction with other genes will increase understanding of DCM in both the dog and the human.

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