Hypomyelinating polyneuropathy (HPN) in Golden Retrievers

Hypomyelinating polyneuropathy (HPN) is a genetically determined disease affecting the peripheral nervous system. In affected individuals, myelin formation is impaired. Clinical signs include muscle weakness, difficulties with walking and coordination, tremors, or loss of reflexes. The disease may appear at a young age and progressively reduce the dog’s quality of life.

In Golden Retrievers, HPN is caused by a nonsense mutation c.1924C>T in the SH3TC2 gene, which plays an important role in the proper function of Schwann cells and myelination of nerve fibers, by a mutation c.1479+1G>A in the MTMR2 gene, which is involved, among other functions, in maintaining myelin integrity, and by a missense mutation c.434T>C in the MPZ gene, which encodes one of the myelin proteins.

1. The inheritance of the mutations c.1924C>T in the SH3TC2 gene and c.1479+1G>A in the MTMR2 gene is likely autosomal recessive. This means that the disease develops only in individuals that inherit the mutated gene from both parents (P/P). Carriers (N/P) are clinically healthy but can pass the mutation to their offspring. When two heterozygous individuals (N/P) are bred, theoretically 25% of the offspring will be healthy (N/N), 50% carriers (N/P), and 25% affected (P/P).

2. The inheritance of the mutation c.434T>C in the MPZ gene is likely autosomal dominant. This means that a single copy of the mutated gene inherited from one parent is sufficient to cause the disease. Individuals with genotypes N/P and P/P are affected. Only individuals with genotype N/N are considered healthy. When two heterozygous individuals (N/P) are bred, theoretically 25% of the offspring will be healthy (N/N), 50% will inherit one copy of the mutation, and 25% will inherit two copies (P/P) and will be affected.

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References:

Cook, S., Hooser, B.N., Williams, D.C., Kortz, G., Aleman, M., Minor, K., Koziol, J., Friedenberg, S.G., Cullen, J.N., Shelton, G.D., Ekenstedt, K.J. : Canine models of Charcot-Marie-Tooth: MTMR2, MPZ, and SH3TC2 variants in golden retrievers with congenital hypomyelinating polyneuropathy. Neuromuscul Disord 33:677-691, 2023. Pubmed reference: 37400349