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New haplotypes in the Bedlington terrier indicate complexity in copper toxicosis

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Abstract

Copper toxicosis (CT) is an autosomal recessive disorder common in Bedlington terriers. Previously, the CT locus was mapped to canine Chromosome (Chr) 10q26 through linkage to marker C04107. Diagnosis, traditionally based on liver biopsy, has recently shifted to interpretation of the C04107 microsatellite alleles where allele 2 segregates with the disease with 90–95% accuracy. Recently, CT has been attributed to a deletion of exon 2 in the MURR1 gene. We also identified a deletion of exon 2 of MURR1 in our collection of 2-2 homozygous affected terriers. However, our collection also included affected 1-1 homozygotes and 1-2 heterozygotes, and these dogs did not have the homozygous deletion. In addition to C04107, we analyzed an adjacent microsatellite (C04107B), and two novel SNPs, all within intron 1 of MURR1, and sequenced all exons and their intronic boundaries. Pedigree analysis indicates that there are two typical haplotypes, one normal and one affected, maintaining complete linkage disequilibrium between C04107 allele 2 and the deletion in most pedigrees. Most importantly, we identified a recombinant haplotype present in a North American pedigree, where allele 2 is not linked with the deletion, and a fourth haplotype containing a splice site variant. Although the splice site alteration appears to be a normal variant, it is present in two affected dogs, which do not carry homozygous deletions of MURR1.

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Acknowledgements

We are grateful to the many breeders who provided samples and information. We thank Shirley Martin and Angela Roper in Canada; Anni-Marjatta Harjula, Sirpa Raitanen, Annika Patama, Tiina Anttinen-Klemetti, Eila Nuutinen, Kirsti and Pauli Koskela, Teuvo Kiili, and Paula Antila (FABALAB) in Finland. We also thank Marja-Leena Akerman for the translation of Finnish text. V.A. Coronado was supported by a graduate scholarship from the National Sciences and Engineering Research Council of Canada (NSERC), and in part by the University of Alberta Medical Sciences Graduate Award and the Faculty of Medicine and Dentistry 75th Anniversary Award. This study was funded by a grant to D.W. Cox by NSERC and the Canadian Genetic Diseases Network (CGDN).

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Correspondence to Diane W. Cox.

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Coronado, V.A., Damaraju, D., Kohijoki, R. et al. New haplotypes in the Bedlington terrier indicate complexity in copper toxicosis . Mamm Genome 14, 483–491 (2003). https://doi.org/10.1007/s00335-002-2255-3

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