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A potentially crucial role of the PKD1 C-terminal tail in renal prognosis.
Higashihara, Eiji; Horie, Shigeo; Kinoshita, Moritoshi; Harris, Peter C; Okegawa, Takatsugu; Tanbo, Mitsuhiro; Hara, Hidehiko; Yamaguchi, Tsuyoshi; Shigemori, Kaori; Kawano, Haruna; Miyazaki, Isao; Kaname, Shinya; Nutahara, Kikuo.
Afiliação
  • Higashihara E; Department of ADPKD Research, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan. ehigashi@ks.kyorin-u.ac.jp.
  • Horie S; Department of Urology, Juntendo University School of Medicine, Tokyo, Japan.
  • Kinoshita M; Diagnostic Division, Development Department, Otsuka Pharmaceutical Co., Ltd, Tokushima, Japan.
  • Harris PC; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
  • Okegawa T; Department of Urology, Kyorin University School of Medicine, Tokyo, Japan.
  • Tanbo M; Department of Urology, Kyorin University School of Medicine, Tokyo, Japan.
  • Hara H; Department of Urology, Kyorin University School of Medicine, Tokyo, Japan.
  • Yamaguchi T; Department of Urology, Kyorin University School of Medicine, Tokyo, Japan.
  • Shigemori K; Department of Urology, Kyorin University School of Medicine, Tokyo, Japan.
  • Kawano H; Department of Urology, Juntendo University School of Medicine, Tokyo, Japan.
  • Miyazaki I; Department of Radiology, Kyorin University School of Medicine, Tokyo, Japan.
  • Kaname S; Department of Nephrology, Kyorin University School of Medicine, Tokyo, Japan.
  • Nutahara K; Department of Urology, Kyorin University School of Medicine, Tokyo, Japan.
Clin Exp Nephrol ; 22(2): 395-404, 2018 Apr.
Article em En | MEDLINE | ID: mdl-28983800
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).
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Rim Policístico Autossômico Dominante / Insuficiência Renal / Canais de Cátion TRPP / Mutação Tipo de estudo: Clinical_trials / Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male País/Região como assunto: Asia Idioma: En Revista: Clin Exp Nephrol Assunto da revista: NEFROLOGIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Japão

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Rim Policístico Autossômico Dominante / Insuficiência Renal / Canais de Cátion TRPP / Mutação Tipo de estudo: Clinical_trials / Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male País/Região como assunto: Asia Idioma: En Revista: Clin Exp Nephrol Assunto da revista: NEFROLOGIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Japão