Gap junction protein gamma 2 (GJC2) gene frameshift deletion in Toy Poodles with hypomyelinating leukodystrophy resembling human Pelizaeus-Merzbacher-like disease 1.

Pelizaeus-Merzbacher-like disease type 1 (PMLD1), also known as hypomyelinating dystrophy 2, is a typical slowly progressive hypomyelinating leukodystrophy (HLD) that manifests in the neonatal period or early infancy. In humans, PMLD1 is inherited as an autosomal recessive trait, with genetic variants identified in the gap junction protein gamma 2 (GJC2) gene. Six juvenile-age Toy Poodle dogs exhibited coarse, vertical head and trunk tremors from immediately after birth. Conventional magnetic resonance imaging revealed uniform signal hyperintensities throughout the subcortical white matter in all dogs. All dogs were euthanized. Subsequent histopathological examination revealed vacuolar changes and demyelination in the cerebral and cerebellar white matter, leading to a diagnosis of HLD. Genetic analysis of five affected dogs identified a shared homozygous 14-base pair deletion in the GJC2 gene, XM_038556433.1:c.920_933del. To the best of our knowledge, this is the first report of a pathogenic GJC2 variant in dogs or any other domestic animal species. The results will enable genetic testing and provide a spontaneous large animal model for the homologous human disease.