Dermatomyositis

Dermatomyositis (DMS) is an inherited inflammatory disease of the skin and muscle. It is most commonly found in Collies and Shetland Sheepdogs, although in Shelties, muscle involvement is less often seen than in Collies. DMS causes skin lesions which can involve skin redness, hair loss, ulcers, crusts, and scaling, most commonly on the face, ears, legs and tail tip. Severe muscle involvement can lead to muscular atrophy and megaesophagus, whereas milder muscle involvement includes weakness in the muscles.

The onset of the disease is most often within the first few years of life, but it can occur later. There may also be triggering factors at play, such as stress, infections, or heat cycles.

Skin lesions can get worse as the disease progresses and can occur chronically.

 


DIAGNOSIS
A diagnosis is reached via a skin biopsy. Sometimes a muscle biopsy may be taken in severe cases.

 


TREATMENT
There are drugs to treat the disease, although they vary in effectiveness case by case. Sometimes, euthanasia is the only option for a dog who is severely affected when the drugs have minimal effect.

 


GENETIC TEST
DMS is caused by a mutant allele in three loci, which are genes PAN2, MAP3K7CL, and DLA-DRB1. The genetic test for DMS gives us the information on whether the dog has a normal allele or the mutant risk allele for all three of those genes. To make it easier to understand, it gives us the results in the form of 6 letters - two each of A, B, and C, where some are capitals and some are lower case. These letters correspond to the aforementioned loci: A to PAN2, B to MAP3K7CL, and C to DLA-DRB1. 

Normal (wild type) alleles are lower case 'a' and 'b', and 'at risk' alleles are upper case 'A' and 'B'. The 'at risk' allele at DLA-DRB1 is represented by a capital C and is 002:01, and the lower case c is any alternate allele.

Each combination of letters has been found to have a different level of risk for DMS. 


​Dermatomyositis (DMS) by ASSA.org (
link) with DMS Genotype calculator for theoretical breeding results

Low Risk Results
aabbCc
aabbCC
AabbCc
AabbCC
aaBbcc
aaBbCc
aaBbCC
AaBbCC
aaBBCc

Moderate Risk Results (up to 50% of dogs with these results developed DMS)
AAbbCc
AAbbCC
aaBBCC
AaBBCc
AABbCc

High Risk Results (over 90% of dogs with these results developed DMS)
​AaBBCC
AABbCC
AABBCc
AABBCC


​RESULTS IN PRACTICE
'It is recommended that breeding pairs be selected on their genotypes at locus A and B. Ideally, matings that could produce puppies with high risk genotypes (AABB, AABb, and AaBB) should be avoided. For example, if a bitch’s genotype is AAbb, it is recommended that she be bred to a dog with one of the following genotypes: aaBB, aaBb, or aabb. This mating will not produce puppies that are homozygous for A or B. Any aa-- genotype can be crossed with any --bb genotype without producing moderate or high risk genotypes, and aabb genotypes can likewise be crossed with any genotype. In general, a dog with a genotype of aabb can be bred to any other genotype to produce low risk puppies.' ASSA, Dermatomyositis (DMS) 
link 

MHC Haplotypes and DMS

Understanding the Major Histocompatibility Complex (MHC)


​The Major Histocompatibility Complex (MHC) is a key part of an immune system. When a pathogen (which is a microbe that causes disease) enters our body, white blood cells can destroy them. MHC molecules bind to fragments of the pathogen and display them on the surface of the cell. Then the immune system can recognise the intruder and produce an immune response.

In humans, certain MHC alleles are known to be associated with diseases such as certain types of cancer. In fact, more diseases have been associated with the MHC in humans than any other area of the genome (source: 
J. L. Wagner, Journal of Heredity).

Research has also linked the MHC to various conditions in canines, including diabetes: 'there is clearly an MHC association with the disease' (
L. J. Kennedy et al., Tissue Antigens), and even to a dog's response to rabies vaccination (L. J. Kennedy et al., Centre for Integrated Genomic Medical Research).


Haplotypes and Dermatomyositis within the Collie breed
MHC Haplotypes obviously have an effect on diseases in dogs, but what about in Rough and Smooth Collies? Genetic analysis of the gene pool is still being undertaken but the initial results are that the vast majority of collies (seemingly more than 90%) are homozygous for an allele called DLA-DRB1*002:01, which is part of the MHC we have been discussing. That means almost all collies have two copies of this allele, and any other is very rare in the gene pool. This indicates the breed has almost no diversity in haplotypes - it can be said that almost all collies have an MHC and therefore immune system that works in exactly the same way.

The DLA-DRB1*002:01 allele, that almost all collies have,  is the 'at risk' allele on the DLA complex for dermatomyositis (source: 
Optigen). In basic terms, when we look at the results of a DMS test, the big Cs are this allele that almost all collies have, and a small case c is any other allele.

The effect of this? Optigen states that 'homozygosity for DLA-DRB1*002:01 increases the risk of DMS from low to moderate for dogs with an aaBB genotype, and moderate to high (AABb and AaBB)'.

The prevalence of this allele is already having a noticeable effect on collies when it comes to DMS, which is an autoimmune disease. When we look at the study of DMS in collies, we can see the extent of the issues with the DLA in the breed. The researchers 'observed remarkably low DLA diversity among collies, with only three haplotypes present in 225 collies worldwide.' and '91% of collies were homozygous for the haplotype' (
Evans et al.). The conclusion was that 'homozygosity confers increased susceptibility' to DMS.


Merle Collies and DMS
An interesting fact to note is that an 'at risk allele' for DMS, which is called A in the study, was not found in conjunction with the merle coat colour gene: 'Merle was only found in conjunction with a [the not at risk allele]. Accordingly, the Merle phenotype was underrepresented in affected dogs'. In practice this means that merle dogs will always have at least one a (not 'at risk'). The researchers determine that selection for a merle coat pattern would be beneficial to reduce the incidences of DMS. In other words - merle dogs have a decreased risk of DMS.

This doesn't mean that we should only breed merle collies. But knowing this fact about the merle gene and DMS is yet another tool in our belt when it comes to tackle the issue of DMS in the breed.

It also provides another case for the breeding of merle dogs to sable dogs. Merle can only affect eumelanin (black pigment), which is barely displayed in pure homozygous sables, meaning that sable merles are often phenotypically sable (they look like usual sable dogs to the eye), plus they receive the benefits of a potentially lower DMS risk due to the Merle gene.

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