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ADTKD-<jats:italic>REN<\/jats:italic> 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 <jats:italic>in silico<\/jats:italic> 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 <jats:italic>REN<\/jats:italic> mutations outside of renin leader peptide can cause ADTKD and delineates an adult form of ADTKD-<jats:italic>REN<\/jats:italic>, 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-<jats:italic>REN<\/jats:italic>, and possibly more generally in ADTKD.<\/jats:p>","DOI":"10.1038\/s41598-019-48014-6","type":"journal-article","created":{"date-parts":[[2019,8,12]],"date-time":"2019-08-12T10:03:02Z","timestamp":1565604182000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5883-3951","authenticated-orcid":false,"given":"C\u00e9line","family":"Schaeffer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Izzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Vettori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Pasqualetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0384-3700","authenticated-orcid":false,"given":"Davide","family":"Cittaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4527-290X","authenticated-orcid":false,"given":"Dejan","family":"Lazarevic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6700-3001","authenticated-orcid":false,"given":"Gianluca","family":"Caridi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Gnutti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Mazza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2679-6946","authenticated-orcid":false,"given":"Luca","family":"Jovine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Scolari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0544-7042","authenticated-orcid":false,"given":"Luca","family":"Rampoldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,8,12]]},"reference":[{"key":"48014_CR1","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1053\/j.ackd.2016.11.012","volume":"24","author":"AJ Bleyer","year":"2017","unstructured":"Bleyer, A. 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