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Case Report: A Pathogenic Missense Variant of WT1 Cosegregates With Proteinuria in a Six-Generation Chinese Family With IgA Nephropathy

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide. In addition to hematuria, proteinuria is observed in a considerable proportion of patients with IgAN and has proven to be a strong risk factor for disease progression. Although the exact pathog...

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Autores principales: Li, Qianqian, Zhu, Li, Shi, Sufang, Xu, Damin, Lv, Jicheng, Zhang, Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8841721/
https://www.ncbi.nlm.nih.gov/pubmed/35174184
http://dx.doi.org/10.3389/fmed.2021.810940
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author Li, Qianqian
Zhu, Li
Shi, Sufang
Xu, Damin
Lv, Jicheng
Zhang, Hong
author_facet Li, Qianqian
Zhu, Li
Shi, Sufang
Xu, Damin
Lv, Jicheng
Zhang, Hong
author_sort Li, Qianqian
collection PubMed
description Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide. In addition to hematuria, proteinuria is observed in a considerable proportion of patients with IgAN and has proven to be a strong risk factor for disease progression. Although the exact pathogenesis of IgAN is still unclear, genetic factors are widely considered to play a role in its occurrence and development. Here, we investigated a large IgAN-associated pedigree of 47 members belonging to six generations. Two members of the family who presented with proteinuria and hematuria were diagnosed with IgAN through renal biopsy. Four other members also exhibited proteinuria or hematuria but without renal biopsy. Using whole-exome sequencing, we identified a likely pathogenic variant in WT1 (c.1397C>T; p.Ser466Phe) that cosegregated with proteinuria in the affected family members. In addition, another pathogenic variant in NPHS1 (c.3478C>T; p.Arg1160Ter) was identified; however, it did not cosegregate with abnormal proteinuria. Compared to individuals in the pedigree with only one heterozygous WT1 variant (c.1397C>T; p.Ser466Phe), the proband and her younger brother carried an additional WT1 variant (c.1433-10G>A) and presented with a more severe phenotype and rapid progression to end-stage kidney disease. Our findings suggest the WT1 missense variant (c.1397C>T; p.Ser466Phe)-induced primary podocyte injury might contribute to the proteinuria phenotype and IgAN progression in this pedigree.
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spelling pubmed-88417212022-02-15 Case Report: A Pathogenic Missense Variant of WT1 Cosegregates With Proteinuria in a Six-Generation Chinese Family With IgA Nephropathy Li, Qianqian Zhu, Li Shi, Sufang Xu, Damin Lv, Jicheng Zhang, Hong Front Med (Lausanne) Medicine Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide. In addition to hematuria, proteinuria is observed in a considerable proportion of patients with IgAN and has proven to be a strong risk factor for disease progression. Although the exact pathogenesis of IgAN is still unclear, genetic factors are widely considered to play a role in its occurrence and development. Here, we investigated a large IgAN-associated pedigree of 47 members belonging to six generations. Two members of the family who presented with proteinuria and hematuria were diagnosed with IgAN through renal biopsy. Four other members also exhibited proteinuria or hematuria but without renal biopsy. Using whole-exome sequencing, we identified a likely pathogenic variant in WT1 (c.1397C>T; p.Ser466Phe) that cosegregated with proteinuria in the affected family members. In addition, another pathogenic variant in NPHS1 (c.3478C>T; p.Arg1160Ter) was identified; however, it did not cosegregate with abnormal proteinuria. Compared to individuals in the pedigree with only one heterozygous WT1 variant (c.1397C>T; p.Ser466Phe), the proband and her younger brother carried an additional WT1 variant (c.1433-10G>A) and presented with a more severe phenotype and rapid progression to end-stage kidney disease. Our findings suggest the WT1 missense variant (c.1397C>T; p.Ser466Phe)-induced primary podocyte injury might contribute to the proteinuria phenotype and IgAN progression in this pedigree. Frontiers Media S.A. 2022-01-31 /pmc/articles/PMC8841721/ /pubmed/35174184 http://dx.doi.org/10.3389/fmed.2021.810940 Text en Copyright © 2022 Li, Zhu, Shi, Xu, Lv and Zhang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Li, Qianqian
Zhu, Li
Shi, Sufang
Xu, Damin
Lv, Jicheng
Zhang, Hong
Case Report: A Pathogenic Missense Variant of WT1 Cosegregates With Proteinuria in a Six-Generation Chinese Family With IgA Nephropathy
title Case Report: A Pathogenic Missense Variant of WT1 Cosegregates With Proteinuria in a Six-Generation Chinese Family With IgA Nephropathy
title_full Case Report: A Pathogenic Missense Variant of WT1 Cosegregates With Proteinuria in a Six-Generation Chinese Family With IgA Nephropathy
title_fullStr Case Report: A Pathogenic Missense Variant of WT1 Cosegregates With Proteinuria in a Six-Generation Chinese Family With IgA Nephropathy
title_full_unstemmed Case Report: A Pathogenic Missense Variant of WT1 Cosegregates With Proteinuria in a Six-Generation Chinese Family With IgA Nephropathy
title_short Case Report: A Pathogenic Missense Variant of WT1 Cosegregates With Proteinuria in a Six-Generation Chinese Family With IgA Nephropathy
title_sort case report: a pathogenic missense variant of wt1 cosegregates with proteinuria in a six-generation chinese family with iga nephropathy
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8841721/
https://www.ncbi.nlm.nih.gov/pubmed/35174184
http://dx.doi.org/10.3389/fmed.2021.810940
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