A deletion in the VLDLR gene in Eurasier dogs with cerebellar hypoplasia resembling a Dandy-Walker-like malformation (DWLM)

PLoS One. 2015 Feb 10;10(2):e0108917. doi: 10.1371/journal.pone.0108917. eCollection 2015.

Abstract

Dandy-Walker-like malformation (DWLM) is the result of aberrant brain development and mainly characterized by cerebellar hypoplasia. DWLM affected dogs display a non-progressive cerebellar ataxia. Several DWLM cases were recently observed in the Eurasier dog breed, which strongly suggested a monogenic autosomal recessive inheritance in this breed. We performed a genome-wide association study (GWAS) with 9 cases and 11 controls and found the best association of DWLM with markers on chromosome 1. Subsequent homozygosity mapping confirmed that all 9 cases were homozygous for a shared haplotype in this region, which delineated a critical interval of 3.35 Mb. We sequenced the genome of an affected Eurasier and compared it with the Boxer reference genome and 47 control genomes of dogs from other breeds. This analysis revealed 4 private non-synonymous variants in the critical interval of the affected Eurasier. We genotyped these variants in additional dogs and found perfect association for only one of these variants, a single base deletion in the VLDLR gene encoding the very low density lipoprotein receptor. This variant, VLDLR:c.1713delC is predicted to cause a frameshift and premature stop codon (p.W572Gfs*10). Variants in the VLDLR gene have been shown to cause congenital cerebellar ataxia and mental retardation in human patients and Vldlr knockout mice also display an ataxia phenotype. Our combined genetic data together with the functional knowledge on the VLDLR gene from other species thus strongly suggest that VLDLR:c.1713delC is indeed causing DWLM in Eurasier dogs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cerebellar Ataxia / genetics
  • Cerebellar Ataxia / pathology
  • Cerebellar Ataxia / veterinary*
  • Chromosome Mapping
  • Dandy-Walker Syndrome / pathology
  • Dandy-Walker Syndrome / veterinary*
  • Dog Diseases / genetics*
  • Dog Diseases / pathology*
  • Dogs
  • Genome-Wide Association Study
  • Haplotypes / genetics
  • Homozygote
  • Intellectual Disability / genetics
  • Intellectual Disability / pathology
  • Intellectual Disability / veterinary*
  • Molecular Sequence Data
  • Receptors, LDL / genetics*
  • Sequence Analysis, DNA
  • Sequence Deletion / genetics*

Substances

  • Receptors, LDL
  • VLDL receptor

Supplementary concepts

  • Dysequilibrium syndrome

Associated data

  • BioProject/PRJEB6079

Grant support

This study was funded in part by a grant from the Albert-Heim Foundation. T. Leeb received a Humboldt Research Award from the Alexander von Humboldt Foundation. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.