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Missense Mutation in Sterile Motif of Novel Protein SamCystin is Associated with Polycystic Kidney Disease in (cy/+) Rat

Joanna H. Brown^*, Marie-Thérèse Bihoreau^*, Sigrid Hoffmann, Bettina Kränzlin, Iulia Tychinskaya, Nicholas Obermüller, Dirk Podlich, Suzanne N. Boehn, Pamela J. Kaisaki^*, Natalia Megel, Patrick Danoy, Richard R. Copley^*, John Broxholme^*, Ralph Witzgall^||, Mark Lathrop, Norbert Gretz and Dominique Gauguier^*

^* The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Medical Research Centre, Klinikum Mannheim, University of Heidelberg, Mannheim, Germany; Division of Nephrology, Medical Clinic III, University of Frankfurt, Frankfurt, Germany; Centre National de Génotypage, Evry, France; and ^|| Institute for Molecular and Cellular Anatomy, University of Regensburg, Regensburg, Germany

Address correspondence to: Dr. Marie-Thérèse Bihoreau, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. Phone: +44-01-865-287-648; Fax: +44-01-865-287-533; E-mail: bihoreau{at}well.ox.ac.uk

Received for publication June 8, 2005. Accepted for publication August 13, 2005.

Autosomal dominant polycystic kidney disease (PKD) is the most common genetic disease that leads to kidney failure in humans. In addition to the known causative genes PKD1 and PKD2, there are mutations that result in cystic changes in the kidney, such as nephronophthisis, autosomal recessive polycystic kidney disease, or medullary cystic kidney disease. Recent efforts to improve the understanding of renal cystogenesis have been greatly enhanced by studies in rodent models of PKD. Genetic studies in the (cy/+) rat showed that PKD spontaneously develops as a consequence of a mutation in a gene different from the rat orthologs of PKD1 and PKD2 or other genes that are known to be involved in human cystic kidney diseases. This article reports the positional cloning and mutation analysis of the rat PKD gene, which revealed a C to T transition that replaces an arginine by a tryptophan at amino acid 823 in the protein sequence. It was determined that Pkdr1 is specifically expressed in renal proximal tubules and encodes a novel protein, SamCystin, that contains ankyrin repeats and a sterile motif. The characterization of this protein, which does not share structural homologies with known polycystins, may give new insights into the pathophysiology of renal cyst development in patients.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673