Genetic causes of Golden Retriever congenital hypomyelinating polyneuropathy

Myelin is an important component of both central nervous system (CNS) and peripheral nervous system (PNS) by surrounding nerve cells, protecting them and aiding in perpetuation of signal conduction. Myelin deficits can occur either by demyelination (myelin that initially formed properly and was then degraded) or by hypomyelination (myelin never correctly/fully formed at all). Two cases of littermate, full-sibling Golden Retriever (GR) puppies with very young onset (i.e. congenital) had neurological deficits. ¹ Peripheral nerve biopsies revealed myelin sheath changes consistent with a predominantly hypomyelinating neuropathy. Uniquely, this syndrome affected only the PNS. Previously reported hypomyelination syndromes in veterinary patients had either exclusively involved the CNS, or both the CNS and the PNS together. We acquired DNA from 4 GRs presenting with clinical signs as reported; 1 nerve biopsies confirmed these dogs to have a congenital PNS hypomyelinating neuropathy. We performed whole genome sequencing on DNA from each of these 4 dogs. Three causative private variants were identified, each in an excellent functional candidate gene known to cause Charcot-MarieTooth disease in humans: a loss of donor splice site variant in 1 dog, a missense variant in 1 dog, and a premature stop codon shared by 2 dogs. These 3 variants were all absent from > 1,000 canine whole genome sequences of normal dogs, and from > 200 control GRs. While this condition is rare in the GR breed, breeders could use genetic tests for these variants to avoid producing affected puppies. In conclusion, theriogenology contains within its purview inherited congenital diseases. Four cases of congenital hereditary neurological disease in Golden Retrievers, wherein, using modern whole genome sequencing technology, we identified the likely causative mutation in each of them. Therefore, this is important for theriogenology service, as we can now offer each of these 3 variants as genetic tests to Golden Retriever breeders and prevent any more puppies born affected with this condition.

Reference

Braund KG, Mehta JR, Toivio-Kinnucan M, et al: Congenital hypomyelinating polyneuropathy in two Golden Retriever littermates. Vet Pathol 1989;26:202-208.

Acknowledgment:  Supported by Theriogenology Foundation, Morris Animal Foundation, and the Office of the Director, National Institutes of Health (NIH) under award number K010D027051.

This manuscript was originally published in the journal Clinical Theriogenology Vol 12(3) Sept 2020.  Clinical Theriogenology is the official journal of the Society for Theriogenology (SFT) and the American College of Theriogenologists (ACT).  This content has been reproduced on the IVIS website with the explicit permission of the SFT/ACT.