A novel locus for dilated cardiomyopathy maps to canine chromosome 8

Abstract

Dilated cardiomyopathy (DCM), the most common form of cardiomyopathy, often leads to heart failure and sudden death. While a substantial proportion of DCMs are inherited, mutations responsible for the majority of DCMs remain unidentified. A genome-wide linkage study was performed to identify the locus responsible for an autosomal recessive inherited form of juvenile DCM (JDCM) in Portuguese water dogs using 16 families segregating the disease. Results link the JDCM locus to canine chromosome 8 with two-point and multipoint lod scores of 10.8 and 14, respectively. The locus maps to a 3.9-Mb region, with complete syntenic homology to human chromosome 14, that contains no genes or loci known to be involved in the development of any type of cardiomyopathy. This discovery of a DCM locus with a previously unknown etiology will provide a new gene to examine in human DCM patients and a model for testing therapeutic approaches for heart failure.

Figure 1

Pedigree drawing of a PWD family segregating JDCM. No DNA was available for dogs represented by grey shaded symbols. Black boxes or circles indicate affected male and female dogs, respectively; unfilled and gray symbols represent unaffected animals, the diamond shaped symbol represents a puppy born dead. All dogs were purebred PWDs with the exception of dog 124, an unrelated mixed breed dog, and her descendents. N = number of dogs of the indicated sex and phenotype, normal or affected.

Figure 2

The multipoint LOD score curve calculated for CFA8, LOD score indicated on the Y axis, and the relative position based on Mb location on CFA8 indicated on the X axis. The shaded region indicates the JDCM critical region defined by haplotype analysis (see Fig. 3). Markers are named below the X axis.

Figure 3

Pedigree and haplotypes for the informative animals from the single largest sibship used in this study, which is also part of Fig. 1. No DNA was available for dogs represented by shaded symbols. Black boxes or circles indicate affected male and female dogs, respectively; unfilled symbols represent unaffected animals. All dogs were purebred PWDs with the exception of dog 124, an unrelated mixed breed dog. The marker order is from the centromere. The haplotypes from the mutant allele baring chromosomes are boxed. The JDCM critical interval is indicated by gray shading.

Figure 4

Ideogram drawings of HSA14 and CFA8 showing the location of the genes known to be involved in cardiomyopathies or ARVD1. The JDCM critical region, corresponding to parts of HSA14q23–q24, is shaded.