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

Eiji Higashihara, Shigeo Horie, Moritoshi Kinoshita, Peter C Harris, Takatsugu Okegawa, Mitsuhiro Tanbo, Hidehiko Hara, Tsuyoshi Yamaguchi, Kaori Shigemori, Haruna Kawano, Isao Miyazaki, Shinya Kaname, Kikuo Nutahara, Eiji Higashihara, Shigeo Horie, Moritoshi Kinoshita, Peter C Harris, Takatsugu Okegawa, Mitsuhiro Tanbo, Hidehiko Hara, Tsuyoshi Yamaguchi, Kaori Shigemori, Haruna Kawano, Isao Miyazaki, Shinya Kaname, Kikuo Nutahara

Abstract

Background: Autosomal 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.

Methods: We 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.

Results: Mean 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.

Conclusions: Aforementioned findings indicate that CTT domain's crucial role in renal prognosis needs further investigation by larger studies (ClinicalTrials.gov; NCT02322385).

Keywords: Autosomal dominant polycystic kidney disease (ADPKD); Genotype/phenotype correlation; PKD1 mutation; Renal survival.

Conflict of interest statement

Funding

Otsuka Pharmaceutical Co., Ltd., provided funding for performing this study.

Conflict of interest

Employment: MK is an employee of Otsuka Pharmaceutical. Grants received: EH and SH received funding from Otsuka Pharmaceutical. Other authors declare that they do not have any conflicts of interest directly relevant to the contents of this manuscript.

Human and animal rights

Informed consent was obtained from all individual participants included in the study. The study protocol adhered to the Declaration of Helsinki, and was approved by the institutional review boards of Kyorin University and Juntendo University (nos. 579 and 14-043, respectively).

Registration of clinical trials

This study is registered in ClinicalTrials.gov under accession no. NCT02322385.

Figures

Fig. 1
Fig. 1
Kaplan–Meier analysis, showing survival curves of non-ADPKD family members and of patients with PKD2 and PKD1 mutations. Mean ± SE survival is significantly different among non-ADPKD family members (81.7 ± 1.2 years), patients with PKD2 mutations (76.3 ± 1.9 years), and patients with PKD1 mutations (69.7 ± 1.1 years) (log rank test, P < 0.0001). PKD genic mutations severely affect patient survival, as well as renal survival
Fig. 2
Fig. 2
Renal survival plots of carriers of PKD1 non-truncating- and truncating-type mutations. PKD1 mutation types affect renal survival (log rank test, P = 0.0348). The mean age difference is 4.3 years. The different renal survival is explained by the complete or incomplete inactivation of PKD1
Fig. 3
Fig. 3
Position (5′- versus 3′-region, divided at nucleotide #7978) of a truncating- and b non-truncating-type mutations, showing different effects on renal survival. b The position of non-truncating-type mutations has a significant influence (log rank test, P = 0.0014), whereas a that of truncating-type mutations does not have a significant influence (log rank test, P = 0.4375). This difference might be due to the uniform inactivation of the CTT domain, irrespective of the position of the mutation in a, compared to the variability of CTT inactivation in b, based on the location of mutation sites. See Fig. 4
Fig. 4
Fig. 4
Kaplan–Meier analysis, showing renal survival curves of patients with PKD1 non-truncating-type mutations in the GPS-upstream domain, transmembrane domain, and CTT domain. Mean ± SE renal survival is significantly different among patients with non-truncating-type mutations in the GPS-upstream domain (70.2 ± 1.5 years), in the transmembrane domain (67.0 ± 2.2 years), and in the CTT domain (50.1 ± 1.7 years) (log rank test, P < 0.0001). This figure indicates a possible crucial role of the CTT domain in PC1 function

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