A potentially crucial role of the PKD1 C-terminal tail in renal prognosis

Abstract

BackgroundAutosomal dominant polycystic disease (ADPKD) often results in renal failure. Recently, allelic influences of PKD1 mutation types on renal survival were extensively investigated. Here, we analyzed integrated influences of PKD1 mutation types and positions on renal survival.MethodsWe included 338 (82 pedigrees) and 72 (12 pedigrees) patients with PKD1 and PKD2 mutations, respectively, identified through comprehensive gene analysis of 101 probands with ADPKD. Genetic testing was performed using next-generation sequencing, long-range PCR, and multiplex ligation-dependent probe amplification. Pathogenic mutations were identified by a software package-integrated seven databases and provided access to five cloud-based computing systems.ResultsMean renal survivals of carriers with PKD1 non-truncating-type mutations at positions upstream of G-protein-coupled receptor proteolytic site (GPS-upstream domain), transmembrane domain, or cytoplasmic C-terminal tail (CTT) domain were 70.2, 67.0, and 50.1 years, respectively (P < 0.0001); renal survival was shorter for mutation positions closer to CTT domain, suggesting its crucial role in renal prognosis. Furthermore, in truncating-type mutations, strong inactivation is anticipated on nucleotides downstream from the mutation site, implying CTT domain inactivation irrespective of mutation site. Shorter mean renal survival was found for PKD1 truncating-type than non-truncating-type mutation carriers (P = 0.0348); mean renal survival was not different between PKD1 3′- and 5′-region truncating-type mutation carriers (P = 0.4375), but was shorter in PKD1 3′-region than in 5′-region non-truncating-type mutation carriers (P = 0.0014). Variable strength of CTT domain inactivation might account for these results.ConclusionsAforementioned findings indicate that CTT domain’s crucial role in renal prognosis needs further investigation by larger studies (ClinicalTrials.gov; NCT02322385).Electronic supplementary materialThe online version of this article (doi:10.1007/s10157-017-1477-7) contains supplementary material, which is available to authorized users.

Age- and height-adjusted total kidney volume growth rate in autosomal dominant polycystic kidney diseases

“…Renal and extrarenal phenotypes of ADPKD are heterogeneous due to the varieties of PKD mutation types [13, 15, 16], modifying genetic factors [17], gender differences [18] and environmental factors [19]. Genetic, imaging, clinical, laboratory, and environmental predictors are factors that are related to determining ADPKD disease severity [20].…”

“…The influences of PKD mutations types on AHTKV-α and measured HtTKV slopes were compared for 88 patients with previously characterized PKD mutations [13]. …”

Prediction of Renal Prognosis in Patients with Autosomal Dominant Polycystic Kidney Disease Using PKD1/PKD2 Mutations

“…Several studies have reported differences in renal prognosis by genotype [8][9][10][11][12][13]19]. The kidney survival rate depends on the causal genes (PKD1, PKD2) and differences between truncating or non-truncating mutations.…”

“…The kidney survival rate depends on the causal genes (PKD1, PKD2) and differences between truncating or non-truncating mutations. Patients with PKD1 mutations, particularly those with truncating mutations, show poor prognosis [8][9][10][11][12][13]19]. However, the relationship between differences in disease progression and mutation types, such as nonsense, frameshift, splicing mutation, and large deletions as truncating mutations, substitution, and in-frame deletion as non-truncating mutations, is unknown.…”

“…Rossetti et al evaluated kidney survival by the age of reaching ESRD and observed no significant difference between the mutation types [13]. However, subsequent reports indicated that the renal prognosis of patients with truncating mutations is poor [9,10,19,22,23]. Furthermore, a study in which a knock-in mouse model of p.R3277C (RC) was used showed that progression was slower in PKD1 RC/RC mice than in PKD1 RC/null ones [24].…”