title: A deletion in the VLDLR gene in Eurasier dogs with cerebellar hypoplasia resembling a Dandy-Walker-like malformation (DWLM).
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.
authors: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors: Martina
authors: M
authors: Gerber
authors: Section of Neurology, Clinic of Small Animal Medicine, Ludwig-Maximilians-University, 80539 Munich, Germany.
authors: Andrea
authors: A
authors: Fischer
authors: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors: Vidhya
authors: V
authors: Jagannathan
authors: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors: Michaela
authors: M
authors: Drögemüller
authors: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors: Cord
authors: C
authors: Drögemüller
authors: Department of Veterinary Clinical Science, Small Animal Clinic, Justus-Liebig-University, 35392 Giessen, Germany.
authors: Martin J
authors: MJ
authors: Schmidt
authors: Section of Neurology, Clinic of Small Animal Medicine, Ludwig-Maximilians-University, 80539 Munich, Germany.
authors: Filipa
authors: F
authors: Bernardino
authors: Generatio Sol. GmbH, 69115 Heidelberg, Germany.
authors: Eberhard
authors: E
authors: Manz
authors: Section of Clinical and Comparative Neuropathology, Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-University, 80539 Munich, Germany.
authors: Kaspar
authors: K
authors: Matiasek
authors: Tierärztliche Praxis für Neurologie, 97337 Dettelbach, Germany.
authors: Kai
authors: K
authors: Rentmeister
authors: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors: Tosso
authors: T
authors: Leeb
mesh_terms: D000818:Animals; D001483:Base Sequence; D002524:Cerebellar Ataxia / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D002874:Chromosome Mapping; D003616:Dandy-Walker Syndrome / Q000473:pathology / Q000662:veterinary*; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology*; D004285:Dogs; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D008969:Molecular Sequence Data; D011973:Receptors, LDL / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D011973:Receptors, LDL; C036053:VLDL receptor