Linkage Analysis in American Staffordshire Terriers with Hereditary Cerebellar Cortical Degeneration
ACVIM 2008
N.J. Olby1; T. Harris1; P.M. Mehta1; M. Breen1; R. Thomas1; R. Myers2; D. Nielsen2
1College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA; 2Department of Genetics, North Carolina State University, Raleigh, NC, USA

A hereditary neurodegenerative disease affecting primarily the cerebellum has emerged within the American Staffordshire Terrier breed. The late onset of clinical signs and recessive nature of the disease have resulted in widespread dissemination of the causative mutation in the breeding population of dogs. The purpose of this study was to genotype families of affected dogs and to perform linkage analysis to identify the disease locus.

DNA samples and pedigrees were obtained from affected dogs and their relatives by dissemination of information through the Staffordshire Terrier Club of America. Affected individuals and their parents and siblings were genotyped with a genome-wide panel of 315 canine fluorochrome labeled microsatellite markers (representing ~10cM resolution), organized into 69 multiplex PCR groups (MSS-2). PCR fragments were analyzed on an ABI-3700 automated Genetic Analyzer (Applied Biosystems), with amplified fragments visualized by incorporation of a fluorescently labeled PCR primer (Applied Biosystems). Results were analyzed with GeneMapper 3.7 software (Applied Biosystems). Linkage analyses were performed using the "lm_bayes" program from the computer package Morgan. This method utilizes a Markov-chain Monte Carlo (MCMC) approach for estimating pedigree likelihoods using the genotype and phenotype information provided.

DNA samples were obtained from over 60 affected American Staffordshire terriers and 120 of their normal relatives. Forty-eight dogs were genotyped with the MSS-2 panel of microsatellites; positive LOD scores were obtained on seven different chromosomes but the only significant linkage was found on CFA9. Additional microsatellites located in the linked region on CFA9 at approximately 1cM intervals (details obtained from the UC Davis Canine Linkage Map) were genotyped in 92 dogs. In these dogs, the disease locus mapped to CFA9 with a maximum LOD score of 9.4. The linked region extended over the first 23-Mb of the chromosome, but there was a peak of linkage extending over a distance of approximately 3-Mb from markers FH2263 to CAP09S. This region contains the genes for two isoforms of a voltage dependent calcium channel gamma subunit (CACNG1 and 4). The gamma subunit is implicated in both calcium channel and glutamate receptor function. We conclude that cerebellar cortical degeneration in American Staffordshire Terriers maps to CFA9, a region containing a viable candidate gene for the disease. Sequencing of the gene for this calcium channel subunit is underway in affected and normal dogs.

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Natasha Olby


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