A spectrum of mutations in the polycystic kidney disease-2 (PKD2) gene from eight Canadian kindreds.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 1000 live births. Linkage studies have shown that the majority (approximately 85%) of cases are due to mutations in PKD1 on chromosome 16p, while mutations in PKD2 on chromosome 4q account for most of the remaining cases. Locus heterogeneity in ADPKD is known to contribute to differences in disease severity, with PKD1-linked families having earlier onset of end-stage renal disease (ESRD) than PKD2-linked families (mean age at ESRD: 56 versus 70, respectively). In this study, 11 Canadian families with ADPKD were screened for PKD2 mutations. In four families, linkage to PKD2 was previously documented. In the remaining seven smaller families, one or more affected members had late-onset ESRD at age 70 or older. Using single-stranded conformational polymorphism analysis, one affected member from each family was screened for mutations in all 15 exons of PKD2, which were PCR-amplified from genomic templates. A spectrum of mutations was found in approximately 73% (8 of 11) of the families screened, with no difference in the detection rate between the PKD2-linked families and the families with late-onset ESRD. In three unrelated families, insertion or deletion of an adenosine in a polyadenosine tract (i.e., (A)8 at nt 2152-2159) was found on exon 11, suggesting that this mononucleotide repeat tract is prone to mutations from "slipped strand mispairing." All mutations, scattered between exons 1 and 11, are predicted to result in a truncated polycystin 2 that lacks both the calcium-binding EF-hand domain and the two cytoplasmic domains required for the interaction of polycystin 2 with polycystin 1 and with itself. Furthermore, no correlation was found between the location of the mutations in the PKD2 coding sequence and disease severity. Thus, these findings are consistent with other recently published reports and suggest that most PKD2 mutations are inactivating.

PKD2 gene variants in Chinese patients with autosomal dominant polycystic kidney disease

“…In our study, the median age at diagnosis were 30.5 years, which may explain by the reason that most of patients were diagnosed due to asymptomatic screening. Since more younger patients (median age 38.5 years) were enrolled in this study, the incidence of hypertension, nephrolithiasis, macro‐hematuria and proteinuria were also less than previous report 9–13 . Sex influence on renal survival in patients with PKD2 variants have been reported 15 .…”

“…Since more younger patients (median age 38.5 years) were enrolled in this study, the incidence of hypertension, nephrolithiasis, macro-hematuria and proteinuria were also less than previous report. [9][10][11][12][13] Sex influence on renal survival in patients with PKD2 variants have been reported. 15 Although the serum creatinine of male patients were significantly higher than female patients in this study, the level of eGFRs have no difference in two groups, probably due to fewer patients were included to make group comparisons difficult.…”

“…In contrast with PKD1 related ADPKD, PKD2 related ADPKD appears to be a much less severe disorder, which demonstrate that the average age at the onset of ESRD was 74.0 (54.3 in PKD1 related ADPKD) 8 . As the mild phenotype of PKD2 related ADPKD, only a few studies have focused on the clinical features of ADPKD with PKD2 variants in Caucasians patients 9–13 . So far, the clinical features of ADPKD with PKD2 variants in Chinese patients have not been reported.…”

“…8 As the mild phenotype of PKD2 related ADPKD, only a few studies have focused on the clinical features of ADPKD with PKD2 variants in Caucasians patients. [9][10][11][12][13] So far, the clinical features of ADPKD with PKD2 variants in Chinese patients have not been reported.…”

Somatic PKD2 Mutations in Individual Kidney and Liver Cysts Support a “Two-Hit” Model of Cystogenesis in Type 2 Autosomal Dominant Polycystic Kidney Disease

“…The consequence of this mutation at the mRNA level has not been characterized. In contrast, the mutations in patients JHU496 (i.e., C1390T in exon 6; R464X) and UT1500 (i.e., 2125InsA in exon 11; frameshift 720 -724X) are both predicted to be protein truncating (12). Each of these mutations segregated only in the affected members of the family and was not found in at least 100 normal chromosomes.…”