A pedigree-based genetic appraisal of Boxer ARVC and the role of the Striatin mutation

Abstract

The objective of this paper was to investigate by pedigree-based genetic means the origins and inheritance of arrhythmogenic right ventricular cardiomyopathy (ARVC) in UK Boxers and assess the role of the proposed causal mutation in the gene, Striatin (STRN). All ARVC cases traced back to a small number of imported American dogs deriving from the group of Boxers studied by Harpster (1983) to define the disease, strongly suggesting that the disease is the same in the two countries. Dogs with and without the STRN mutation were found in both ARVC affected and normal Boxers showing that the mutation is not responsible for the disease. Evidence was found that the STRN mutation is, however, genetically linked with the gene responsible on the same chromosome. The linkage implies that the two genes can separate by meiotic recombination such that both ARVC-affected and ARVC-unaffected lines of dogs may carry either the STRN mutation or its wild-type allele. These have been found. Homozygotes for the STRN mutation tended to be severely affected at early ages, suggesting that there is an interaction between the known effects of the STRN mutation on the cardiomyocyte and ARVC.

Keywords: Cardiomyopathy; Dogs; Genetics.

FIG 1:

Pedigree chart showing line of descent of dogs transmitting arrhythmogenic right ventricular cardiomyopathy (ARVC) in line 1. Data are representative of the whole line 1 group (24 per cent of the total), and were selected primarily on the basis of having been STRN tested. Squares=males; circles=females; closed symbols=ARVC-affected dogs; shaded symbols=dogs that have produced several cases of ARVC; HOM=homozygous for the STRN mutation; HET=heterozygous for the STRN mutation; WT=dogs carrying the wild-type alleles of STRN. Key ARVC-producing dogs are marked A–F. Age of diagnosis is indicated and also ARVC severity category where attainable. Since all affected cases carry the STRN mutation, it is assumed that the source animal was of this genotype. Only the most informative dogs in terms of age of onset, severity category and STRN genotype are shown

FIG 2:

Pedigree chart showing line of descent of dogs transmitting arrhythmogenic right ventricular cardiomyopathy (ARVC) in line 2. Data are representative of the whole line 2 group (20 per cent of the total) and were selected primarily on the basis of having been STRN tested. Symbols are the same as in Fig 1. Key ARVC-transmitting dogs are marked G–O. Since the majority of dogs in this line are wild type (WT) for STRN, it is likely that the original source animals in this line were of this WT genotype. Possible sites of recombination are marked with red crosses. Only the most informative dogs in terms of age of onset, severity category and STRN genotype are shown

FIG 3:

Diagram depicting the non-random distribution of arrhythmogenic right ventricular cardiomyopathy (ARVC) throughout the Boxer breed in the UK. The three family lines at risk of ARVC and deriving from males imported from the USA are shown, with the original disease-free section of the breed defined by exclusion

FIG 4:

Diagram depicting recombination between the STRN and the arrhythmogenic right ventricular cardiomyopathy (ARVC) loci. Recombination will only be detectable when the transmitting parent is heterozygous at both STRN and ARVC loci, for example, STRN ARVC/++ (mutations in coupling), or STRN+/+ ARVC (mutations in repulsion). Recombination in STRN ARVC/++ parents will yield STRN+/+ ARVC recombinant progeny, and vice versa, but recombinants can only be detected when they are homozygous for an STRN allele, as this is the only way of being sure that the allele in question is located on the same chromosome as the ARVC mutation (see Fig 2). For this reason, STRN heterozygotes are not considered for detecting recombination