Dermatomyositis (DMS) – predisposition to the development of the disease

Dermatomyositis is a multifactorial autoimmune disease. The manifestation of DMS can be caused by both genetic and external factors (e.g., infectious viral diseases, vaccinations, stress, hormonal factors, UV radiation). In affected individuals, the disease causes inflammatory vasculopathy of the skin and muscles. The immune system attacks its own cells and attacks the endothelium of small blood vessels, where inflammation subsequently breaks out and a wide range of processes leading to ischemia occur. This results in characteristic atrophy and necrosis of the epidermis and hair follicles and degeneration of muscle fibres.

The most common clinical symptoms are skin lesions on the head, ears, tail tip, paws, or bony protrusions. Many of these symptoms worsen over time, leading to alopecia and significant expansion of skin lesions. Muscles are weakened by gradual loss of muscle mass. Muscle atrophy occurs, contributing to serious mobility complications.

DMS affects short-haired collies, long-haired collies, bearded collies, border collies, and shelties. Unlike shelties, which are free of subsequent symptoms, collies experience muscle atrophy in the head area and problems with swallowing food and drinking, while muscle atrophy in the limbs leads to an atypical gait with a high step. The age at which the first clinical symptoms appear varies. In some cases, the first symptoms appear at 12 weeks of age, in others only during adulthood.

Research into genetic predispositions to the development of DMS identified a genetic variant in the region of chromosome 10 (PAN2 g.627760G>A = locus A) and an indel in the region of chromosome 31 of the MAP3K7CL gene (c.383_392ACTCCACAAA>GACT = locus B). The study also mapped the highly variable MHC II region, DLA genes (dog leucocyte antigen), where a risk allele of the DLA complex was detected (DLA-DRB1 002:01 = locus C).

Significant differences in allele frequencies were observed in Shetland sheepdogs and collies. Collies had a higher frequency of allele A, while allele B dominated in Shetland sheepdogs. The frequency of detected allele combinations therefore differed significantly between these two breeds.

The combination of these three loci resulted in haplotypes, whose variable combinations classify the risk of developing DMS. Based on the resulting combination of alleles, haplotypes are classified into three groups: haplotypes with a high risk of DMS manifestation, haplotypes with a medium risk of DMS manifestation, and haplotypes with a low risk of DMS manifestation.

Haplotypes with a high risk of disease manifestation (90 – 100 %): AABbCC, AaBBCC, AABBCC, AABBCc
Haplotypes with a middle risk of DMS manifestation (33 – 50 %): AAbbCC, AAbbCc, aaBBCC, AaBBCc, AABbCc
Haplotypes with a low risk of DMS manifestation (0 - 5 %): aabbCC, aabbCc, AabbCC, AabbCc, aaBbCC, aaBbCc, AaBbCC, AaBbCc, aaBBCc

The allelic combinations aabbcc, aaBBcc, Aabbcc, AaBbcc, AaBBcc, AAbbcc, AABbcc, and AABBcc cannot currently be classified into any of the three haplotype groups. The combinations listed occurred sporadically in the study, and therefore it was not possible to reliably assess their risk level and describe their connection with the development of DMS.

Particularly in collies, very low diversity of DLA haplotypes was observed, with only three DLA-DRB1 variants found. The absence of variability made it impossible to search for a deeper association with DMS. More than 90% of the collies tested were homozygous with the result DLA-DRB1: 002:01/002:01. Two dominant DLA haplotypes were detected in Shetland sheepdogs. As with collies, DLA-DRB1: 002:01/002:01 was the most common, mainly due to increased homozygosity. This finding led to the conclusion that DLA-DRB1: 002:01 is a risk allele and its homozygous combination is associated with the development of DMS. The authors believe that almost all purebred collies have an increased predisposition to developing DMS due to the high homozygous representation of DLA-DRB1: 002:01/002:01.

All resulting haplotypes, including those that have not been classified yet, are important data for breeders. Each allelic combination is indicative for the future selection of breeding pairs. Breeders should especially avoid mating of individuals whose offspring could potentially have the following allelic composition in their haplotype: AABB, AABb, and AaBB.

References:
Evans et al. (2017) Beyond the MHC: A canine model of dermatomyositis shows a complex pattern of genetic risk involving novel loci. PLoS Genet 13(2): e1006604. doi:10.1371/journal.pgen.1006604.