Mutations of the human polycystic kidney disease 2 (PKD2) gene

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited nephropathy, usually of late onset (onset between third to seventh decade), primarily characterized by the formation of fluid-filled cysts in the kidneys. It is one of the most frequent inherited conditions affecting approximately 1:1,000 Caucasians. Two major genes have been identified and characterized in detail: PKD1 and PKD2, mapping on chromosomes 16p13.3 and 4q21-23, respectively. A third gene, PKD3, has been implicated in selected families. Polycystic kidney disease of types 1 or 2 follows a very similar course of symptoms, both being multisystem pleiotropic disorders of indistinguishable picture on clinical grounds. The only difference is that patients with PKD2 mutations run a milder course compared to PKD1 carriers, with an average 10-20 years later age of onset and lower probability to reach end-stage-renal failure. The proteins polycystin-1 and -2 are trans-membranous glycoproteins hypothesized to participate in a common signaling pathway, interacting with each other and with other proteins, and coordinately expressed in normal and cystic tissue. Renal cysts most probably arise after a second somatic event, which inactivates the inherited healthy allele of the same gene, or perhaps one of the alleles of the other gene counterpart, generating a trans-heterozygous state. This article reviews the reported mutations in PKD2. Mutations of all kinds have been reported over the entire sequence of the PKD2 gene, with no apparent significant clustering and with some evidence of genotype/phenotype correlation. Most families harbor their own private mutations but a few recurrent events have been reported in unrelated families.

Mutation Analysis of Autosomal Dominant Polycystic Kidney Disease Genes in Han Chinese

“…Four nonsense mutations were identified, two each in PKD1 and PKD2 . Among them, a 50905 C→T mutation in PKD1 and a 2407 C→T substitution in PKD2 has once been reported [16, 23, 24, 25]. A representative example is seen in figure 6, which depicts a 2407 C→T PKD2 mutation in pedigree H3.…”

PIGEA-14, a Novel Coiled-coil Protein Affecting the Intracellular Distribution of Polycystin-2

“…It is generally acknowledged that the COOH terminus of polycystin-2 harbors a retention signal for the endoplasmic reticulum (10), and because many mutations in the PKD2 gene are predicted to lead to the synthesis of a truncated protein (14), the mislocalization of a mutant polycystin-2 protein and the resulting aberrant calcium currents could be one explanation for the formation of cysts. Our two-hybrid screen using the COOH terminus of polycystin-2 as a bait has led to the identification of PIGEA-14, a novel coiled-coil protein not only interacting with polycystin-2 but also with itself and with GM130.…”

“…Furthermore a retention signal for the endoplasmic reticulum has been identified in the COOH terminus of polycystin-2 (10). Because many mutations in the PKD2 gene are predicted to lead to the synthesis of a truncated protein (14), a possible scenario could be that a mutant protein escapes from the endoplasmic reticulum and reaches the plasma membrane, where it results in the uncontrolled influx of Ca 2ϩ ions. One entry point to a better functional understanding of polycystin-2 lies in the identification of interacting proteins.…”

Four novel mutations of the PKD2 gene in czech families with autosomal dominant polycystic kidney disease

“…At least three different genes are involved. PKD1 locus (MIM Peters et al, 1993), and so far, 57 different germline mutations and 46 somatic mutations were identified (Deltas et al, 2001). The mutations are dispersed over the entire coding sequence without a particular hot spot, except that no mutations have been found in exons 3, 9, and 15.…”