Genetic mutation causing neonatal ataxia in Coton de Tulear dogs

Abstract

BACKGROUND: Bandera's neonatal ataxia (BNAt) is an autosomal recessive cerebellar ataxia that affects members of the Coton de Tulear dog breed. OBJECTIVE: To identify the mutation that causes BNAt. ANIMALS: The study involved DNA from 112 Cotons de Tulear (including 15 puppies with signs of BNAt) and 87 DNA samples from dogs of 12 other breeds. METHODS: The BNAt locus was mapped with a genome-wide association study (GWAS). The coding exons of positional candidate gene GRM1, which encodes metabotropic glutamate receptor 1, were polymerase chain reaction (PCR)-amplified and resequenced. A 3-primer PCR assay was used to genotype individual dogs for a truncated retrotransposon inserted into exon 8 of GRM1. RESULTS: The GWAS indicated that the BNAt locus was in a canine chromosome 1 region that contained candidate gene GRM1. Resequencing this gene from BNAt-affected puppies indicated that exon 8 was interrupted by the insertion of a 5'-truncated retrotransposon. All 15 BNAt-affected puppies were homozygous for the insert, whereas all other Cotons de Tulear were heterozygotes (n = 43) or homozygous (n = 54) for the ancestral allele. None of the 87 dogs from 12 other breeds had the insertion allele. CONCLUSIONS AND CLINICAL IMPORTANCE: BNAt is caused by a retrotransposon inserted into exon 8 of GRM1. A DNA test for the GRM1 retrotransposon insert can be used for genetic counseling and to confirm the diagnosis of BNAt.