Genetics of fibrotic myopathy in the German Shepherd Dog
Emily Binversie DVM, MS, NIH T32 Post-Doctoral Scholar
Peter Muir BVSc, PhD, Diplomate ACVS, FRCVS
Melita Grunow Family Professor of Companion Animal Health
Comparative Orthopaedic & Genetics Research Laboratory, University of Wisconsin-Madison, School of Veterinary Medicine, 2015 Linden Drive, Madison, WI 53706
Fibrotic myopathy is a very specific clinical syndrome with a highly characteristic presentation of profound hindlimb lameness and fibrous contracture of medial thigh musculature. Affected dogs typically experience life-long disability as the muscle fibrosis and contracture is not reversible with treatment. Most cases are German Shepherd Dogs, particularly males. Fibrotic myopathy is extremely rare in other breeds, but has been diagnosed in 3 Doberman Pinschers, 2 Belgian Shepherds, 1 St. Bernard, and 1 Old English Sheepdog. This marked breed predisposition suggests the disease is genetic. Fibrotic myopathy is likely a simple (Mendelian) genetic disease in which a single mutation causes the condition.
Clinical presentation of fibrotic myopathy
Fibrotic myopathy is diagnosed from physical examination of the patient. Young adult dogs are most often affected by slowly developing hindlimb lameness, possibly with a history of injury. Dogs may be affected bilaterally. Affected hindlimbs have a shortened stride with a rapid elastic medial rotation of the foot, external rotation of the hock and internal rotation of the stifle during the swing phase [Lewis, 1997]. The gait is caused by altered stifle (knee) and hock (ankle) range of motion. Palpation of the medial thigh reveals a characteristic firm taut band extending from the midline of the pelvis, where the gracilis muscle originates, or the ischiatic tuberosity, where the semitendinosus muscle originates, to the caudomedial aspect of the stifle. The gracilis muscle is usually more severely affected than the semitendinosus. Palpation of the affected muscles is often painful.
Treatment of fibrotic myopathy and prognosis
Prognosis for affected dogs is very poor. There is no effective treatment and dogs experience permanent disability. Surgical cutting of the fibrotic band in the thigh is unsuccessful as the contracture recurs within a few months. Medical therapy is generally unsuccessful, although, anecdotally, stem cell injections may help mobility over time.
What causes fibrotic myopathy?
It has been suggested that trauma to thigh muscles may lead to muscle fibrosis and scarring. In this regard it is interesting that racing Greyhounds often develop gracilis rupture as an athletic injury but do not develop fibrotic myopathy. Over the years there have been many suggestions regarding the cause of the disease, but supportive evidence is lacking.
Fibrotic myopathy has features in common with congenital muscular torticollis in humans, where unilateral fibrotic contracture of a neck muscle cases causes torticollis and abnormal head and neck positioning. Congenital muscular torticollis is considered a recessive Mendelian disease in humans although a causal mutation has not been identified.
Work at the University of Wisconsin-Madison
The Comparative Orthopaedic & Genetics Research Laboratory (http://www.vetmed.wisc.edu/lab/corl) is undertaking work to discover the genetic basis of fibrotic myopathy in the German Shepherd Dog. The first step in this work is to develop a high-quality German Shepherd Dog breed-specific reference genome assembly
Breed-specific de novo assembly of the GSD genome. The canine genome was first assembled from a Boxer in 2005 [Lindblad-Toh, 2005]. This assembly remains the primary reference for the Canis lupus familiaris family (canFam3.1). Use of a single, inbred Boxer as a reference genome results in bias; samples of DNA from other dogs may appear more similar to the reference, and sample variation from different populations can be underestimated. Substantial differences in genomic structural variation between breeds, could substantially impair genomic dissection of a rare breed-related canine genetic disease.
In March 2019, we won the Plant and Animal Genomics video competition and undertook sequencing and de novo assembly to obtain a high-quality breed-specific genome assembly for the GSD (https://www.pacb.com/smrt-science/smrt-grant/).
We recruited a purebred female German Shepherd Dog of mixed American and German lines for this phase of the project. Using the PacBio Sequel II platform, we generated 189Gb of sequencing data at ~76x coverage of the canine genome. De novo assembly of the sequencing data has yielded a high-quality phased breed-specific assembly for the German Shepherd Dog. In the future, this work will also enable investigation of the genetic contribution to other important breed-associated diseases in the GSD, such as hip and elbow dysplasia amongst other examples.
Whole genome resequencing of fibrotic myopathy case and control German Shepherd Dogs. New DNA sequencing methods available in the last few years have substantially enabled whole genome sequencing in dogs at lower costs with superior sequencing data. Newer generation long-read and linked-read sequencing platforms (Pacific Biosciences, Oxford Nanopore Technologies, 10x Genomics) enable improved analysis of genomic variation between individual dogs but have not yet been used for genomic dissection of disease in the dog.
Now that a draft breed-specific genome assembly for the German Shepherd Dog is available, we are now undertaking a genetic discovery project to find what causes fibrotic myopathy. We will do this by obtaining DNA from blood samples collected from 5-10 German Shepherd Dogs affected with fibrotic myopathy and 5-10 German Shepherd Dogs that are phenotype-negative controls over the age of 9 years.
Potential Impact on German Shepherd Dog Health
After successful completion of this work, we expect to discover the genetic basis of fibrotic myopathy. A genetic screening test can easily be developed after completion of the sequencing work.
Can my dog participate in the study?
Fibrotic Myopathy Cases. To be considered a fibrotic myopathy case, your dog must have clinical changes characteristic of the disease as described above identified from patient examination.
Control Group. If your German Shepherd Dog is 9 years or older and has never had any muscle problems and is a purebred dog with a pedigree, your dog will be eligible as a control dog.
If your dog fits the above case or control categories, and you are interested in participating or wish to learn more about this work, please contact Dr. Emily Binversie, or Dr. Peter Muir at firstname.lastname@example.org.
We will send you:
- Instructions about how to get a blood sample to us at UW Madison for DNA isolation
- A consent form to be signed indicating approval of study participation
Please send us:
- The blood sample if you do not come to UW Madison to visit with the Genetics Service
- The completed consent form
- Any pedigree information you may have on your dog. Pedigree information will be used to determine whether any study dogs are related.
- Photographs or videos of any dogs affected with fibrotic myopathy
- Veterinary examination records of your dog confirming fibrotic myopathy
Lewis DD, Shelton GD, Piras A, et al. Gracilis or semitendinosus myopathy in 18 dogs. J Am Anim Hosp Assoc 1997;33:177-188.
Lindblad-Toh K, Wade CM, Mikkelsen TS, et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 2005;438:803–819.