Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein

Abstract Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a genetically heterogeneous renal disorder leading to progressive loss of renal function. ADTKD-REN is due to rare mutations in renin, all localized in the protein leader peptide and affecting its co-translational insertion in...

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Autores principales:	Céline Schaeffer, Claudia Izzi, Andrea Vettori, Elena Pasqualetto, Davide Cittaro, Dejan Lazarevic, Gianluca Caridi, Barbara Gnutti, Cinzia Mazza, Luca Jovine, Francesco Scolari, Luca Rampoldi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8dc16d1b7739477cbf9a5b1523e9ce60
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spelling	oai:doaj.org-article:8dc16d1b7739477cbf9a5b1523e9ce602021-12-02T16:08:46ZAutosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein10.1038/s41598-019-48014-62045-2322https://doaj.org/article/8dc16d1b7739477cbf9a5b1523e9ce602019-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-48014-6https://doaj.org/toc/2045-2322Abstract Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a genetically heterogeneous renal disorder leading to progressive loss of renal function. ADTKD-REN is due to rare mutations in renin, all localized in the protein leader peptide and affecting its co-translational insertion in the endoplasmic reticulum (ER). Through exome sequencing in an adult-onset ADTKD family we identified a new renin variant, p.L381P, mapping in the mature protein. To assess its pathogenicity, we combined genetic data, computational and predictive analysis and functional studies. The L381P substitution affects an evolutionary conserved residue, co-segregates with renal disease, is not found in population databases and is predicted to be deleterious by in silico tools and by structural modelling. Expression of the L381P variant leads to its ER retention and induction of the Unfolded Protein Response in cell models and to defective pronephros development in zebrafish. Our work shows that REN mutations outside of renin leader peptide can cause ADTKD and delineates an adult form of ADTKD-REN, a condition which has usually its onset in childhood. This has implications for the molecular diagnosis and the estimated prevalence of the disease and points at ER homeostasis as a common pathway affected in ADTKD-REN, and possibly more generally in ADTKD.Céline SchaefferClaudia IzziAndrea VettoriElena PasqualettoDavide CittaroDejan LazarevicGianluca CaridiBarbara GnuttiCinzia MazzaLuca JovineFrancesco ScolariLuca RampoldiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-11 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Céline Schaeffer Claudia Izzi Andrea Vettori Elena Pasqualetto Davide Cittaro Dejan Lazarevic Gianluca Caridi Barbara Gnutti Cinzia Mazza Luca Jovine Francesco Scolari Luca Rampoldi Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein
description	Abstract Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a genetically heterogeneous renal disorder leading to progressive loss of renal function. ADTKD-REN is due to rare mutations in renin, all localized in the protein leader peptide and affecting its co-translational insertion in the endoplasmic reticulum (ER). Through exome sequencing in an adult-onset ADTKD family we identified a new renin variant, p.L381P, mapping in the mature protein. To assess its pathogenicity, we combined genetic data, computational and predictive analysis and functional studies. The L381P substitution affects an evolutionary conserved residue, co-segregates with renal disease, is not found in population databases and is predicted to be deleterious by in silico tools and by structural modelling. Expression of the L381P variant leads to its ER retention and induction of the Unfolded Protein Response in cell models and to defective pronephros development in zebrafish. Our work shows that REN mutations outside of renin leader peptide can cause ADTKD and delineates an adult form of ADTKD-REN, a condition which has usually its onset in childhood. This has implications for the molecular diagnosis and the estimated prevalence of the disease and points at ER homeostasis as a common pathway affected in ADTKD-REN, and possibly more generally in ADTKD.
format	article
author	Céline Schaeffer Claudia Izzi Andrea Vettori Elena Pasqualetto Davide Cittaro Dejan Lazarevic Gianluca Caridi Barbara Gnutti Cinzia Mazza Luca Jovine Francesco Scolari Luca Rampoldi
author_facet	Céline Schaeffer Claudia Izzi Andrea Vettori Elena Pasqualetto Davide Cittaro Dejan Lazarevic Gianluca Caridi Barbara Gnutti Cinzia Mazza Luca Jovine Francesco Scolari Luca Rampoldi
author_sort	Céline Schaeffer
title	Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein
title_short	Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein
title_full	Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein
title_fullStr	Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein
title_full_unstemmed	Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein
title_sort	autosomal dominant tubulointerstitial kidney disease with adult onset due to a novel renin mutation mapping in the mature protein
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/8dc16d1b7739477cbf9a5b1523e9ce60
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Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein

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