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.
<h4>Background</h4>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 f...
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2017-01-01
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| Online Access: | https://doi.org/10.1371/journal.pone.0174274 |
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| author | Konstantinos Voskarides Charalambos Stefanou Myrtani Pieri Panayiota Demosthenous Kyriakos Felekkis Maria Arsali Yiannis Athanasiou Dimitris Xydakis Kostas Stylianou Eugenios Daphnis Giorgos Goulielmos Petros Loizou Judith Savige Martin Höhne Linus A Völker Thomas Benzing Patrick H Maxwell Daniel P Gale Mathias Gorski Carsten Böger Barbara Kollerits Florian Kronenberg Bernhard Paulweber Michalis Zavros Alkis Pierides Constantinos Deltas |
| author_facet | Konstantinos Voskarides Charalambos Stefanou Myrtani Pieri Panayiota Demosthenous Kyriakos Felekkis Maria Arsali Yiannis Athanasiou Dimitris Xydakis Kostas Stylianou Eugenios Daphnis Giorgos Goulielmos Petros Loizou Judith Savige Martin Höhne Linus A Völker Thomas Benzing Patrick H Maxwell Daniel P Gale Mathias Gorski Carsten Böger Barbara Kollerits Florian Kronenberg Bernhard Paulweber Michalis Zavros Alkis Pierides Constantinos Deltas |
| author_sort | Konstantinos Voskarides |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results and conclusions</h4>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. |
| format | Article |
| id | doaj-art-4982e92e8e3548db842cd64fd672e4a6 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-4982e92e8e3548db842cd64fd672e4a62025-08-20T03:26:34ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01123e017427410.1371/journal.pone.0174274A functional variant in NEPH3 gene confers high risk of renal failure in primary hematuric glomerulopathies. Evidence for predisposition to microalbuminuria in the general population.Konstantinos VoskaridesCharalambos StefanouMyrtani PieriPanayiota DemosthenousKyriakos FelekkisMaria ArsaliYiannis AthanasiouDimitris XydakisKostas StylianouEugenios DaphnisGiorgos GoulielmosPetros LoizouJudith SavigeMartin HöhneLinus A VölkerThomas BenzingPatrick H MaxwellDaniel P GaleMathias GorskiCarsten BögerBarbara KolleritsFlorian KronenbergBernhard PaulweberMichalis ZavrosAlkis PieridesConstantinos Deltas<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results and conclusions</h4>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.https://doi.org/10.1371/journal.pone.0174274 |
| spellingShingle | Konstantinos Voskarides Charalambos Stefanou Myrtani Pieri Panayiota Demosthenous Kyriakos Felekkis Maria Arsali Yiannis Athanasiou Dimitris Xydakis Kostas Stylianou Eugenios Daphnis Giorgos Goulielmos Petros Loizou Judith Savige Martin Höhne Linus A Völker Thomas Benzing Patrick H Maxwell Daniel P Gale Mathias Gorski Carsten Böger Barbara Kollerits Florian Kronenberg Bernhard Paulweber Michalis Zavros Alkis Pierides Constantinos Deltas 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 |
| 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. |
| title_full | 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. |
| title_fullStr | 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. |
| title_full_unstemmed | 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. |
| title_short | 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. |
| title_sort | functional variant in neph3 gene confers high risk of renal failure in primary hematuric glomerulopathies evidence for predisposition to microalbuminuria in the general population |
| url | https://doi.org/10.1371/journal.pone.0174274 |
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