A frameshift-deletion mutation in Reelin causes cerebellar hypoplasia in White Swiss Shepherd dogs

Anim Genet. 2023 Oct;54(5):632-636. doi: 10.1111/age.13336. Epub 2023 Jun 19.

Abstract

Cerebellar hypoplasia is a heterogeneous neurological condition in which the cerebellum is smaller than usual or not completely developed. The condition can have genetic origins, with Mendelian-effect mutations described in several mammalian species. Here, we describe a genetic investigation of cerebellar hypoplasia in White Swiss Shepherd dogs, where two affected puppies were identified from a litter with a recent common ancestor on both sides of their pedigree. Whole genome sequencing was conducted for 10 dogs in this family, and filtering of these data based on a recessive transmission hypothesis highlighted five protein-altering candidate variants - including a frameshift-deletion of the Reelin (RELN) gene (p.Val947*). Given the status of RELN as a gene responsible for cerebellar hypoplasia in humans, sheep and mice, these data strongly suggest the loss-of-function variant as underlying these effects. This variant has not been found in other dog breeds nor in a cohort of European White Swiss Shepherds, suggesting a recent mutation event. This finding will support the genotyping of a more diverse sample of dogs, and should aid future management of the harmful allele through optimised mating schemes.

Keywords: RELN; Reelin; canine; cerebellar hypoplasia; dogs; mutation; neurological development; whole genome sequencing.

MeSH terms

  • Animals
  • Cerebellum / abnormalities
  • Dog Diseases* / genetics
  • Dogs
  • Frameshift Mutation
  • Humans
  • Mammals
  • Mutation
  • Reelin Protein* / genetics
  • Sequence Deletion
  • Switzerland

Substances

  • Reelin Protein

Supplementary concepts

  • Cerebellar Hypoplasia

Associated data

  • RefSeq/XM_038562771.1
  • RefSeq/XP_038418699.1
  • RefSeq/XM_038562736.1
  • RefSeq/XM_038566048.1
  • RefSeq/XM_038565308.1
  • RefSeq/XM_038567212.1