Published in:
Open Access
01-04-2018 | Original article
A potentially crucial role of the PKD1 C-terminal tail in renal prognosis
Authors:
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
Published in:
Clinical and Experimental Nephrology
|
Issue 2/2018
Login to get access
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).