A deletion in the VLDLR gene in Eurasier dogs with cerebellar hypoplasia resembling a Dandy-Walker-like malformation (DWLM).
- Gerber M Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
- Fischer A Section of Neurology, Clinic of Small Animal Medicine, Ludwig-Maximilians-University, 80539 Munich, Germany.
- Jagannathan V Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
- Drögemüller M Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
- Drögemüller C Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
- Schmidt MJ Department of Veterinary Clinical Science, Small Animal Clinic, Justus-Liebig-University, 35392 Giessen, Germany.
- Bernardino F Section of Neurology, Clinic of Small Animal Medicine, Ludwig-Maximilians-University, 80539 Munich, Germany.
- Manz E Generatio Sol. GmbH, 69115 Heidelberg, Germany.
- Matiasek K Section of Clinical and Comparative Neuropathology, Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-University, 80539 Munich, Germany.
- Rentmeister K Tierärztliche Praxis für Neurologie, 97337 Dettelbach, Germany.
- Leeb T Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
- 2015-02-11
Published in:
- PloS one. - 2015
Animals
Base Sequence
Cerebellar Ataxia
Chromosome Mapping
Dandy-Walker Syndrome
Dog Diseases
Dogs
Genome-Wide Association Study
Haplotypes
Homozygote
Intellectual Disability
Molecular Sequence Data
Receptors, LDL
Sequence Analysis, DNA
Sequence Deletion
English
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.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.1371/journal.pone.0108917
- PMID 25668033
- Persistent URL
- https://sonar.ch/global/documents/178177
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