Human Molecular Genetics Advance Access originally published online on October 7, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 23 3043-3053
DOI: 10.1093/hmg/ddg336
© 2003 Oxford University Press
A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog
1Norwegian School of Veterinary Science, PO Box 8146 N-0033 Oslo, Norway, 2Clinical and Human Biology Divisions, Fred Hutchinson Cancer Research Center, PO Box 19024, D4-100, Seattle, WA 98109-1024, USA, 3The Institute for Genomic Research, 9712 Medical Center Drive, Rockville, MD 20850, USA, 4UMR 6061 CNRS, Génétique et Développement, Faculté de Médecine, 35043 Rennes Cédex, France, 5Laboratory of Immunobiology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA, 6Basic Research Program, SAIC-Frederick, Inc., National Cancer Institute Frederick, Frederick, MD 21702, USA, 7Oncology Research, Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk CB8 7UU, UK and 8Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA
Received June 26, 2003; Revised September 23, 2003; Accepted September 29, 2003
Hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a naturally occurring canine kidney cancer syndrome that was originally described in German Shepherd dogs. The disease is characterized by bilateral, multifocal tumors in the kidneys, uterine leiomyomas and nodules in the skin consisting of dense collagen fibers. We previously mapped RCND to canine chromosome 5 (CFA5) with a highly significant LOD score of 16.7 (
=0.016). We have since narrowed the RCND interval following selection and RH mapping of canine genes from the 1.3x canine genome sequence. These sequences also allowed for the isolation of gene-associated BACs and the characterization of new microsatellite markers. Ordering of newly defined markers and genes with regard to recombinants localizes RCND to a small chromosomal region that overlaps the human Birt–Hogg–Dubé locus, suggesting the same gene may be responsible for both the dog and the phenotypically similar human disease. We herein describe a disease-associated mutation in exon 7 of canine BHD that leads to the mutation of a highly conserved amino acid of the encoded protein. The absence of recombinants between the disease locus and the mutation in US and Norwegian dogs separated by several generations is consistent with this mutation being the disease-causing mutation. Strong evidence is provided that the RCND mutation may have a homozygous lethal effect (P<0.01).
* To whom correspondence should be addressed at: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., D4-100, PO Box 19024 Seattle, WA 98109-1024, USA. Tel: +1 2066676979; Fax: +1 2066676396; Email: eostrand{at}fhcrc.org
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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