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Title: A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher

Author
item MEURS, KATHRYN - Washington State University
item LAHMERS, SUNSHINE - Washington State University
item KEENE, BRUCE - North Carolina State University
item White, Stephen
item OYAMA, MARK - University Of Pennsylvania
item MAUCELI, EVAN - Broad Institute Of Mit/harvard
item LINDBLAD-TOH, KERSTIN - Broad Institute Of Mit/harvard

Submitted to: Human Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/8/2012
Publication Date: 8/1/2012
Citation: Meurs, K.M., Lahmers, S., Keene, B.W., White, S.N., Oyama, M.A., Mauceli, E., Lindblad-Toh, K. 2012. A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher. Human Genetics. 131(8):1319-25.

Interpretive Summary: Dilated cardiomyopathy (DCM) is a heart disease that can result in the development of congestive heart failure and sudden cardiac death in both human beings and dogs. DCM is often a familial disease, and at least 30 different human genes have been found to harbor mutations that can cause DCM. The Doberman pinscher dog is one of the most commonly reported breeds with familial DCM, and we have previously shown that DCM is inherited as an autosomal dominant trait in Dobermans. A genomewide association scan (GWAS) was conducted in 48 Doberman DCM cases and 48 Doberman controls defined as individuals aged at least 10 years without evidence of DCM. This GWAS identified a significant genome region on canine chromosome 14 (genomewide P<0.009). The pyruvate dehydrogenase kinase 4 (PDK4) gene was located within this region, and sequencing revealed a 16 base pair deletion at a splice site, an intron/exon boundary within the gene. Mutations in or near gene splice sites can interfere with messenger RNA processing, and can change the ultimate protein produced from a gene. This particular deletion was highly associated with DCM (P<0.0001) in 66 Doberman cases and 66 Doberman controls, but was not observed in 100 controls from 11 additional breeds. Gene expression analysis confirmed that this deletion led to an altered messenger RNA, and electron microscopy of cardiac cells showed severe mitochondrial problems consistent with inactive PDK4. Taken together these data indicate that PDK4 variants can be involved in DCM and provide a strongly associated genetic variant for DCM diagnostic testing of Doberman pinschers.

Technical Abstract: Familial dilated cardiomyopathy is a primary myocardial disease that can result in the development of congestive heart failure and sudden cardiac death. Spontaneous animal models of familial dilated cardiomyopathy exist and the Doberman pinscher dog is one of the most commonly reported canine breeds. The objective of this study was to evaluate familial dilated cardiomyopathy in the Doberman pinscher dog using a genome-wide association study for a genetic alteration(s) associated with the development of this disease in this canine model. Genomewide association analysis identified an area of statistical significance on canine chromosome 14 (praw = 9.999e-05 corrected for genome-wide significance), fine-mapping of additional SNPs flanking this region localized a signal to 23,774,190–23,781,919 (p = 0.001) and DNA sequencing identified a 16-base pair deletion in the 50 donor splice site of intron 10 of the pyruvate dehydrogenase kinase 4 gene in affected dogs (p<0.0001). Electron microscopy of myocardium from affected dogs demonstrated disorganization of the Z line, mild to moderate T tubule and sarcoplasmic reticulum dilation, marked pleomorphic mitochondrial alterations with megamitochondria, scattered mitochondria with whorling and vacuolization and mild aggregates of lipofuscin granules. In conclusion, we report the identification of a splice site deletion in the PDK4 gene that is associated with the development of familial dilated cardiomyopathy in the Doberman pinscher dog.