#apaperaday: Current Classification of Canine Muscular Dystrophies and Identification of New Variants

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Current Classification of Canine Muscular Dystrophies and Identification of New Variants

Today’s pick is a paper by Shelton et al from Genes MDPI on genetic muscular dystrophies in dogs and the identification of new mutations in the dog DMD gene. Like in humans, spontaneous variants occur also in dogs. DOI: 10.3390/genes14081557

There are dozens of different genetic muscular dystrophies in humans. Authors here focus on muscular dystrophies in dogs. In both humans and dogs, next-generation sequencing has helped identify variants. In humans, the clinical symptoms of muscular dystrophies are well described.

In dogs, there is less known about the symptoms and there is not a one-to-one correlation between human and dog symptoms, e.g., symptoms in dystrophinopathies in dogs may present very early in puppies, more similar to congenital muscular dystrophy in humans.

Authors outline the different types of muscular dystrophy: dystrophinopathies, limb girdle muscular dystrophies (>40 different genes), Emery-Dreifuss muscular dystrophy, facioscapulo muscular dystrophy, myotonic dystrophy, and oculo-pharyngeal muscular dystrophy.

In dogs, muscular dystrophies have been reported. Authors list a table with the various forms reported in the literature containing 20 DMD mutations, but also sarcoglycanopathy, collagen 6 mutations, lama2 mutations, and LARGE1 mutations.

Thus the variety seen in human genes is also there in dogs. What is interesting for DMD is that most (almost all) variants are small exonic variants, while in humans most variants are large deletions. I wonder which gene differences or replication differences cause this.

After this review-like introduction, authors then also report new variants in the DMD genes for several dogs, where it had been confirmed that dystrophin was absent in skeletal muscle (biopsy or autopsy material). Dogs showed pathology early on, with macroglossia (enlarged tongue).

Dogs also had problems swallowing and breathing. There was also weakness in the legs, with some dogs unable to stand due to weakness and contractures. In the biopsy/autopsy, the histology showed skeletal muscle pathology, no dystrophin, increased utrophin, and embryonic myosin.

Authors found a nonsense mutation in exon 55, a retrotransposon in intron 20 (likely resulting in cryptic splicing but this was not confirmed) and an insertion in exon 23 that caused a frameshift. These variants were reported in different dog breeds.

Authors discuss for one of the breeds (French bulldog) muscular dystrophy had been reported before without finding the mutations. It is possible that this dog had the same variant as the one found here. The challenge with X-linked diseases is that they can fly below the radar.

Usually, females will not have pathology, while part of the male offspring will have the mutation. With dog breeding only a limited pool of dogs is used for the breeding, which means that these mutations can persist. Authors outline ideally better screening is done.

From a research perspective, the muscle but also the brains of the dogs would be very interesting to study. Often, however, when the dogs are this sick, they will be euthanized and not studied further (as a pet owner I can relate).

Some spontaneously occurring dog models are being used to study & develop treatments, e.g., the golden retriever muscular dystrophy dog (GRMD), a dog model that needs dog dystrophin exon 50 skipping but also a dog for myotubular myopathy that was used to develop gene therapy.

For Duchenne, especially the GRMD model has been very useful to improve the AAV gene therapy in Duchenne, where it was helpful to translate from a 20 gram mouse to a 20 kg human. Obviously, these studies need to be carefully considered from an ethical standpoint.

The focus of the authors is more on identifying variants from a veterinary perspective (which makes sense as that is their background), but of course, I have my own angle 🙂