title: Missense mutation in sterile alpha motif of novel protein SamCystin is associated with polycystic kidney disease in (cy/+) rat.
abstract: 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 alpha 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.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Joanna H
authors.initials: JH
authors.lastname: Brown
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Bihoreau
authors.forename: Sigrid
authors.initials: S
authors.lastname: Hoffmann
authors.forename: Bettina
authors.initials: B
authors.lastname: Kränzlin
authors.forename: Iulia
authors.initials: I
authors.lastname: Tychinskaya
authors.forename: Nicholas
authors.initials: N
authors.lastname: Obermüller
authors.forename: Dirk
authors.initials: D
authors.lastname: Podlich
authors.forename: Suzanne N
authors.initials: SN
authors.lastname: Boehn
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Kaisaki
authors.forename: Natalia
authors.initials: N
authors.lastname: Megel
authors.forename: Patrick
authors.initials: P
authors.lastname: Danoy
authors.forename: Richard R
authors.initials: RR
authors.lastname: Copley
authors.forename: John
authors.initials: J
authors.lastname: Broxholme
authors.forename: Ralph
authors.initials: R
authors.lastname: Witzgall
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauguier
mesh_terms: D000818:Animals; D001483:Base Sequence; D018076:DNA, Complementary / Q000032:analysis; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000819:agonists; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000473:pathology*; D012313:RNA / Q000032:analysis; D051381:Rats; D011914:Rats, Inbred BN; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D050396:TRPP Cation Channels
chemical_list: D018076:DNA, Complementary; D008565:Membrane Proteins; D009687:Nuclear Proteins; D012313:RNA; D050396:TRPP Cation Channels; C532259:Anks6 protein, rat