Missense Mutation in Sterile α 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 ␣ 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.

Transgenic Overexpression of Anks6 Causes Polycystic Kidney Disease in Rats

“…The aggravated morphology was associated with an extremely increased renal hypertrophy (Figure 3, A-D). 8 …”

“…Apoptotic figures and mitotic cells were a prominent feature of the developing kidney up to the age of 3 to 4 weeks in both lines and were barely seen in the wild-type ) rats (C). The rats were genotyped with RT-PCR by using primers specific to the transgene and primers specific to the endogenous mutation as described in Brown et al 8 *P Ͻ 0.01; **P Ͻ 0.001.…”

“…2 Although the cystic phenotype and possible therapeutic interventions are extensively investigated, [3][4][5][6][7] the gene Anks6, which is mutated in cystic PKD/Mhm rats, was identified only recently. 8 Anks6, which is different from any of the known PKD-related genes, consists of 16 exons with 2655 bp coding for an 885-amino acid protein including10 tandem ankyrin repeats at its N-terminus and a sterile ␣ motif (SAM) domain at its C-terminus. 8 A missense mutation (CϾT) in this gene (Anks6 (p.R823W) ) accounts for the exchange of a highly conserved arginine residue with a tryptophan residue at amino acid 823 within the SAM domain, and it is tightly linked to the cystic phenotype.…”

“…8 Anks6, which is different from any of the known PKD-related genes, consists of 16 exons with 2655 bp coding for an 885-amino acid protein including10 tandem ankyrin repeats at its N-terminus and a sterile ␣ motif (SAM) domain at its C-terminus. 8 A missense mutation (CϾT) in this gene (Anks6 (p.R823W) ) accounts for the exchange of a highly conserved arginine residue with a tryptophan residue at amino acid 823 within the SAM domain, and it is tightly linked to the cystic phenotype. The function of Anks6 is still unknown, but the presence of the ankyrin repeats and SAM domain suggests a function in protein interaction and/or protein binding, such as scaffolding.…”

Mutations in ANKS6 Cause a Nephronophthisis-Like Phenotype with ESRD

“…22 Furthermore, an Anks6 (p.R823W) mutation was recently found to cause the cystic phenotype in the PKD/Mhm(cy/+) rat, a widely used animal model of human PKD. 23 The role of Wnt signaling is well established in cystic kidney diseases. [24][25][26] The canonical b-catenin pathway and the planar cell polarity pathway recently received attention for their roles in multiple cellular processes within the kidney.…”