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

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 i...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Singapore 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838153/
https://www.ncbi.nlm.nih.gov/pubmed/28983800
http://dx.doi.org/10.1007/s10157-017-1477-7
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author 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
author_facet 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
author_sort Higashihara, Eiji
collection PubMed
description 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). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10157-017-1477-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-58381532018-03-09 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 Clin Exp Nephrol Original Article 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). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10157-017-1477-7) contains supplementary material, which is available to authorized users. Springer Singapore 2017-10-05 2018 /pmc/articles/PMC5838153/ /pubmed/28983800 http://dx.doi.org/10.1007/s10157-017-1477-7 Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
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
A potentially crucial role of the PKD1 C-terminal tail in renal prognosis
title A potentially crucial role of the PKD1 C-terminal tail in renal prognosis
title_full A potentially crucial role of the PKD1 C-terminal tail in renal prognosis
title_fullStr A potentially crucial role of the PKD1 C-terminal tail in renal prognosis
title_full_unstemmed A potentially crucial role of the PKD1 C-terminal tail in renal prognosis
title_short A potentially crucial role of the PKD1 C-terminal tail in renal prognosis
title_sort potentially crucial role of the pkd1 c-terminal tail in renal prognosis
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838153/
https://www.ncbi.nlm.nih.gov/pubmed/28983800
http://dx.doi.org/10.1007/s10157-017-1477-7
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