Universität zu Köln

Voskarides, Konstantinos ORCID: 0000-0002-3705-3451, Stefanou, Charalambos, Pieri, Myrtani, Demosthenous, Panayiota, Felekkis, Kyriakos, Arsali, Maria, Athanasiou, Yiannis, Xydakis, Dimitris, Stylianou, Kostas, Daphnis, Eugenios, Goulielmos, Giorgos, Loizou, Petros, Savige, Judith, Hoehne, Martin, Voelker, Linus A., Benzing, Thomas, Maxwell, Patrick H., Gale, Daniel P., Gorski, Mathias, Boeger, Carsten, Kollerits, Barbara, Kronenberg, Florian ORCID: 0000-0003-2229-1120, Paulweber, Bernhard, Zavros, Michalis, Pierides, Alkis and Deltas, Constantinos ORCID: 0000-0001-5549-9169 (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). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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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 longterm 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 microalbuminuria.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Voskarides, Konstantinos UNSPECIFIED orcid.org/0000-0002-3705-3451 UNSPECIFIED Stefanou, Charalambos UNSPECIFIED UNSPECIFIED UNSPECIFIED Pieri, Myrtani UNSPECIFIED UNSPECIFIED UNSPECIFIED Demosthenous, Panayiota UNSPECIFIED UNSPECIFIED UNSPECIFIED Felekkis, Kyriakos UNSPECIFIED UNSPECIFIED UNSPECIFIED Arsali, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Athanasiou, Yiannis UNSPECIFIED UNSPECIFIED UNSPECIFIED Xydakis, Dimitris UNSPECIFIED UNSPECIFIED UNSPECIFIED Stylianou, Kostas UNSPECIFIED UNSPECIFIED UNSPECIFIED Daphnis, Eugenios UNSPECIFIED UNSPECIFIED UNSPECIFIED Goulielmos, Giorgos UNSPECIFIED UNSPECIFIED UNSPECIFIED Loizou, Petros UNSPECIFIED UNSPECIFIED UNSPECIFIED Savige, Judith UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoehne, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Voelker, Linus A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Benzing, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Maxwell, Patrick H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gale, Daniel P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gorski, Mathias UNSPECIFIED UNSPECIFIED UNSPECIFIED Boeger, Carsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Kollerits, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Kronenberg, Florian UNSPECIFIED orcid.org/0000-0003-2229-1120 UNSPECIFIED Paulweber, Bernhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Zavros, Michalis UNSPECIFIED UNSPECIFIED UNSPECIFIED Pierides, Alkis UNSPECIFIED UNSPECIFIED UNSPECIFIED Deltas, Constantinos UNSPECIFIED orcid.org/0000-0001-5549-9169 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-236372
DOI:	10.1371/journal.pone.0174274
Journal or Publication Title:	PLoS One
Volume:	12
Number:	3
Date:	2017
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FOCAL SEGMENTAL GLOMERULOSCLEROSIS; ENDOPLASMIC-RETICULUM STRESS; CHRONIC KIDNEY-DISEASE; FAMILIAL HEMATURIA; SLIT DIAPHRAGM; MUTATIONS; PROTEINURIA; PROGRESSION; COL4A4; MODEL Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23637