A mixed breed dog with neuronal ceroid lipofuscinosis is homozygous for a CLN5 nonsense mutation previously identified in Border Collies and Australian Cattle Dogs

摘要

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by progressive declines in neurological functions following normal development. The NCLs are distinguished from similar disorders by the accumulation of autofluorescent lysosomal storage bodies in neurons and many other cell types, and are classified as lysosomal storage diseases. At least 13 genes contain pathogenic sequence variants that underlie different forms of NCL. Naturally occurring canine NCLs can serve as models to develop better understanding of the disease pathologies and for preclinical evaluation of therapeutic interventions for these disorders. To date 14 sequence variants in 8 canine orthologs of human NCL genes have been found to cause progressive neurological disorders similar to human NCLs in 12 different dog breeds. A mixed breed dog with parents of uncertain breed background developed progressive neurological signs consistent with NCL starting at approximately 11 to 12 months of age, and when evaluated with magnetic resonance imaging at 21 months of age exhibited diffuse brain atrophy. Due to the severity of neurological decline the dog was euthanized at 23 months of age. Cerebellar and cerebral cortical neurons contained massive accumulations of autofluorescent storage bodies the contents of which had the appearance of tightly packed membranes. A whole genome sequence, generated with DNA from the affected dog contained a homozygous C-to-T transition at position 30,574,637 on chromosome 22 which is reflected in the mature CLN5 transcript (CLN5: c.619C > 7) and converts a glutamine codon to a termination codon (p.Gln207Ter). The identical nonsense mutation has been previously associated with NCL in Border Collies, Australian Cattle Dogs, and a German Shepherd Australian Cattle Dog mix. The current whole genome sequence and a previously generated whole genome sequence for an Australian Cattle Dog with NCL share a rare homozygous haplotype that extends for 87 kb surrounding 22: 30, 574, 637 and includes 21 polymorphic sites. When genotyped at 7 of these polymorphic sites, DNA samples from the German Shepherd-Australian Cattle Dog mix and from 5 Border Collies with NCL that were homozygous for the CLN5: c.619 T allele also shared this homozygous haplotype, suggesting that the NCL in all of these dogs stems from the same founding mutation event that may have predated the establishment of the modern dog breeds. If so, the CLN5 nonsence allele is probably segregating in other, as yet unidentified, breeds. Thus, dogs exhibiting similar NCL-like signs should be screened for this CLN5 nonsense allele regardless of breed.