eprintid: 1546390 rev_number: 23 eprint_status: archive userid: 608 dir: disk0/01/54/63/90 datestamp: 2017-04-27 10:45:27 lastmod: 2021-09-23 22:53:51 status_changed: 2017-04-27 10:45:27 type: article metadata_visibility: show creators_name: Voskarides, K creators_name: Stefanou, C creators_name: Pieri, M creators_name: Demosthenous, P creators_name: Felekkis, K creators_name: Arsali, M creators_name: Athanasiou, Y creators_name: Xydakis, D creators_name: Stylianou, K creators_name: Daphnis, E creators_name: Goulielmos, G creators_name: Loizou, P creators_name: Savige, J creators_name: Höhne, M creators_name: Völker, LA creators_name: Benzing, T creators_name: Maxwell, PH creators_name: Gale, DP creators_name: Gorski, M creators_name: Böger, C creators_name: Kollerits, B creators_name: Kronenberg, F creators_name: Paulweber, B creators_name: Zavros, M creators_name: Pierides, A creators_name: Deltas, C title: A functional variant in NEPH3 gene confers high risk of renal failure in primary hematuric glomerulopathies. Evidence for predisposition to microalbuminuria in the general population ispublished: pub divisions: UCL divisions: B02 divisions: C10 divisions: D17 divisions: G93 keywords: Variant genotypes, Microalbuminuria, Chronic kidney disease, Human genetics, Proteinuria, Meta-analysis, Genetics of disease, Genotyping note: Copyright © 2017 Voskarides et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. abstract: BACKGROUND: Recent data emphasize that thin basement membrane nephropathy (TBMN) should not be viewed as a form of benign familial hematuria since chronic renal failure (CRF) and even end-stage renal disease (ESRD), is a possible development for a subset of patients on long-term follow-up, through the onset of focal and segmental glomerulosclerosis (FSGS). We hypothesize that genetic modifiers may explain this variability of symptoms. METHODS: We looked in silico for potentially deleterious functional SNPs, using very strict criteria, in all the genes significantly expressed in the slit diaphragm (SD). Two variants were genotyped in a cohort of well-studied adult TBMN patients from 19 Greek-Cypriot families, with a homogeneous genetic background. Patients were categorized as "Severe" or "Mild", based on the presence or not of proteinuria, CRF and ESRD. A larger pooled cohort (HEMATURIA) of 524 patients, including IgA nephropathy patients, was used for verification. Additionally, three large general population cohorts [Framingham Heart Study (FHS), KORAF4 and SAPHIR] were used to investigate if the NEPH3-V353M variant has any renal effect in the general population. RESULTS AND CONCLUSIONS: Genotyping for two high-scored variants in 103 TBMN adult patients with founder mutations who were classified as mildly or severely affected, pointed to an association with variant NEPH3-V353M (filtrin). This promising result prompted testing in the larger pooled cohort (HEMATURIA), indicating an association of the 353M variant with disease severity under the dominant model (p = 3.0x10-3, OR = 6.64 adjusting for gender/age; allelic association: p = 4.2x10-3 adjusting for patients' kinships). Subsequently, genotyping 6,531 subjects of the Framingham Heart Study (FHS) revealed an association of the homozygous 353M/M genotype with microalbuminuria (p = 1.0x10-3). Two further general population cohorts, KORAF4 and SAPHIR confirmed the association, and a meta-analysis of all three cohorts (11,258 individuals) was highly significant (p = 1.3x10-5, OR = 7.46). Functional studies showed that Neph3 homodimerization and Neph3-Nephrin heterodimerization are disturbed by variant 353M. Additionally, 353M was associated with differential activation of the unfolded protein response pathway, when overexpressed in stressed cultured undifferentiated podocyte cells, thus attesting to its functional significance. Genetics and functional studies support a "rare variant-strong effect" role for NEPH3-V353M, by exerting a negative modifier effect on primary glomerular hematuria. Additionally, genetics studies provide evidence for a role in predisposing homozygous subjects of the general population to micro-albuminuria. date: 2017-03-23 date_type: published official_url: http://doi.org/10.1371/journal.pone.0174274 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1267836 doi: 10.1371/journal.pone.0174274 pii: PONE-D-16-49857 lyricists_name: Gale, Daniel lyricists_id: DGALE18 actors_name: Bracey, Alan actors_id: ABBRA90 actors_role: owner full_text_status: public publication: PLoS One volume: 12 number: 3 article_number: e0174274 event_location: United States issn: 1932-6203 citation: Voskarides, K; Stefanou, C; Pieri, M; Demosthenous, P; Felekkis, K; Arsali, M; Athanasiou, Y; ... Deltas, C; + view all <#> Voskarides, K; Stefanou, C; Pieri, M; Demosthenous, P; Felekkis, K; Arsali, M; Athanasiou, Y; Xydakis, D; Stylianou, K; Daphnis, E; Goulielmos, G; Loizou, P; Savige, J; Höhne, M; Völker, LA; Benzing, T; Maxwell, PH; Gale, DP; Gorski, M; Böger, C; Kollerits, B; Kronenberg, F; Paulweber, B; Zavros, M; Pierides, A; Deltas, C; - view fewer <#> (2017) A functional variant in NEPH3 gene confers high risk of renal failure in primary hematuric glomerulopathies. Evidence for predisposition to microalbuminuria in the general population. PLoS One , 12 (3) , Article e0174274. 10.1371/journal.pone.0174274 <https://doi.org/10.1371/journal.pone.0174274>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1546390/1/journal.pone.0174274.pdf