An ABCC9 Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs

Figures

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  Figure 1. Right ventricle from a juvenile Manchester Terrier showing patchy regions of pallor in the myocardium (arrows). HE, scale = 200 µm. Upper inset: In these areas, there is myofiber degeneration and loss with replacement by connective tissue and scant mononuclear cells. Degenerate myofibers are present in the upper right half of the inset and are small (attenuated) with flocculent cytoplasm. Normal myofibers are evident at the lower right corner for comparison. HE, scale = 20 µm. Lower inset: Staining with Masson’s trichrome demonstrates collagen deposition (blue) in the affected regions. Scale = 20 µm.

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  Figure 2. Photographs of two closely related dog breeds affected by sudden cardiac death of the young and dilated cardiomyopathy: (a) Manchester Terrier dog; (b) English Toy Terrier dog.

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  Figure 3. Manhattan plot of a mixed model genome-wide association study for sudden cardiac death in the young and dilated cardiomyopathy in 12-case and 36-control Manchester Terrier dogs. There is a strong signal on chromosome 27 (p = 5 × 10−17 Wald test) at a locus that harbors genes encoding subunits of an ATP-sensitive cardiac potassium channel (ABCC9 and KCNJ8). Single nucleotide polymorphisms above the black dotted line achieved a p value < 10−8.

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  Figure 4. Representative Sanger sequencing electropherograms for wild-type, heterozygous, and homozygous affected genotypes for the ABCC9 p.R1186Q variant (ENSCAFT00000043641.4 c.3557G > A) associated with sudden cardiac death in the young and dilated cardiomyopathy in a natural dog model.