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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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 30 - and 50 -region truncating-type mutation carriers (P = 0.4375), but was shorter in PKD1 30 -region than in 50 -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).

Original languageEnglish (US)
Pages (from-to)395-404
Number of pages10
JournalClinical and Experimental Nephrology
Issue number2
StatePublished - Jan 1 2018


  • Autosomal dominant polycystic kidney disease (ADPKD)
  • Genotype/phenotype correlation
  • PKD1 mutation
  • Renal survival

ASJC Scopus subject areas

  • Physiology
  • Nephrology
  • Physiology (medical)


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