Human Molecular Genetics, 2002, Vol. 11, No. 16 1823-1833
© 2002 Oxford University Press
Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3
1Center for Canine Genetics and Reproduction, James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA, 2Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center 1100 Fairview Avenue North, D4-100 Seattle, WA 98109, USA, 3Molecular and Cellular Biology Program, University of Washington, Box 357275, Seattle, WA 98195-7275, USA and 4Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK
Received March 18, 2002; Accepted May 30, 2002
Cone degeneration (cd ) is an autosomal recessive canine disease that occurs naturally in the Alaskan Malamute and German Shorthaired Pointer breeds. It is phenotypically similar to human achromatopsia, a heterogeneous autosomal recessive disorder associated with three distinct loci. Both the canine disease and its human counterparts are characterized by day-blindness and absence of retinal cone function in adults. We report linkage of the canine cd locus to marker C29.002 on canine chromosome 29 at recombination fraction 
=0.0 with a maximum LOD score of 24.68 in a series of informative outbred pedigrees derived from cd-affected Alaskan Malamutes. Conserved gene order between CFA29 and the long arm of human chromosome 8 argued for homology between the cd locus and the human achromatopsia locus, ACHM3, at 8q21–22. The canine homolog of the cyclic nucleotide-gated channel ß-subunit gene (CNGB3), responsible for the human ACHM3 disease phenotype, was mapped within the zero-recombination interval for the cd locus. A deletion removing all exons of canine CNGB3 was identified in cd-affected Alaskan Malamute-derived dogs. A missense mutation in exon 6 (D262N, nucleotide 784) within a conserved region of the same gene was detected in German Shorthaired Pointers affected with an allelic disorder. Identification of these canine disorders as homologs of human ACHM3 underscores the power of recent developments in canine genomics, and provides a valuable system for exploring disease mechanisms and evaluating potential therapeutic measures in disorders of cone photoreceptors.
* To whom correspondence should be addressed. Tel: +1 6072565684; Fax: +1 6072565689; Email: gma2{at}cornell.edu (GMA): Tel: +1 2266676979; Fax: +1 6072565689; Email: eostrand@fred.fhcrc.org(EAO).
AF490511 (canine CNGB3), BH760135 (BAC 100-O2, SP6 end sequence) and BH760136 (BAC 100-O2, T7 end sequence) The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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