Cargando…

LAMA2 and LOXL4 are candidate FSGS genes

BACKGROUND: Focal and segmental glomerulosclerosis (FSGS) is a histologic pattern of injury that characterizes a wide spectrum of diseases. Many genetic causes have been identified in FSGS but even in families with comprehensive testing, a significant proportion remain unexplained. METHODS: In a fam...

Descripción completa

Detalles Bibliográficos
Autores principales: Vijayan, Poornima, Hack, Saidah, Yao, Tony, Qureshi, Mohammad Azfar, Paterson, Andrew D., John, Rohan, Davenport, Bernard, Lennon, Rachel, Pei, York, Barua, Moumita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474709/
https://www.ncbi.nlm.nih.gov/pubmed/34565340
http://dx.doi.org/10.1186/s12882-021-02524-6
_version_ 1784575277396918272
author Vijayan, Poornima
Hack, Saidah
Yao, Tony
Qureshi, Mohammad Azfar
Paterson, Andrew D.
John, Rohan
Davenport, Bernard
Lennon, Rachel
Pei, York
Barua, Moumita
author_facet Vijayan, Poornima
Hack, Saidah
Yao, Tony
Qureshi, Mohammad Azfar
Paterson, Andrew D.
John, Rohan
Davenport, Bernard
Lennon, Rachel
Pei, York
Barua, Moumita
author_sort Vijayan, Poornima
collection PubMed
description BACKGROUND: Focal and segmental glomerulosclerosis (FSGS) is a histologic pattern of injury that characterizes a wide spectrum of diseases. Many genetic causes have been identified in FSGS but even in families with comprehensive testing, a significant proportion remain unexplained. METHODS: In a family with adult-onset autosomal dominant FSGS, linkage analysis was performed in 11 family members followed by whole exome sequencing (WES) in 3 affected relatives to identify candidate genes. RESULTS: Pathogenic variants in known nephropathy genes were excluded. Subsequently, linkage analysis was performed and narrowed the disease gene(s) to within 3% of the genome. WES identified 5 heterozygous rare variants, which were sequenced in 11 relatives where DNA was available. Two of these variants, in LAMA2 and LOXL4, remained as candidates after segregation analysis and encode extracellular matrix proteins of the glomerulus. Renal biopsies showed classic segmental sclerosis/hyalinosis lesion on a background of mild mesangial hypercellularity. Examination of basement membranes with electron microscopy showed regions of dense mesangial matrix in one individual and wider glomerular basement membrane (GBM) thickness in two individuals compared to historic control averages. CONCLUSIONS: Based on our findings, we postulate that the additive effect of digenic inheritance of heterozygous variants in LAMA2 and LOXL4 leads to adult-onset FSGS. Limitations to our study includes the absence of functional characterization to support pathogenicity. Alternatively, identification of additional FSGS cases with suspected deleterious variants in LAMA2 and LOXL4 will provide more evidence for disease causality. Thus, our report will be of benefit to the renal community as sequencing in renal disease becomes more widespread. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12882-021-02524-6.
format Online
Article
Text
id pubmed-8474709
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-84747092021-09-28 LAMA2 and LOXL4 are candidate FSGS genes Vijayan, Poornima Hack, Saidah Yao, Tony Qureshi, Mohammad Azfar Paterson, Andrew D. John, Rohan Davenport, Bernard Lennon, Rachel Pei, York Barua, Moumita BMC Nephrol Research Article BACKGROUND: Focal and segmental glomerulosclerosis (FSGS) is a histologic pattern of injury that characterizes a wide spectrum of diseases. Many genetic causes have been identified in FSGS but even in families with comprehensive testing, a significant proportion remain unexplained. METHODS: In a family with adult-onset autosomal dominant FSGS, linkage analysis was performed in 11 family members followed by whole exome sequencing (WES) in 3 affected relatives to identify candidate genes. RESULTS: Pathogenic variants in known nephropathy genes were excluded. Subsequently, linkage analysis was performed and narrowed the disease gene(s) to within 3% of the genome. WES identified 5 heterozygous rare variants, which were sequenced in 11 relatives where DNA was available. Two of these variants, in LAMA2 and LOXL4, remained as candidates after segregation analysis and encode extracellular matrix proteins of the glomerulus. Renal biopsies showed classic segmental sclerosis/hyalinosis lesion on a background of mild mesangial hypercellularity. Examination of basement membranes with electron microscopy showed regions of dense mesangial matrix in one individual and wider glomerular basement membrane (GBM) thickness in two individuals compared to historic control averages. CONCLUSIONS: Based on our findings, we postulate that the additive effect of digenic inheritance of heterozygous variants in LAMA2 and LOXL4 leads to adult-onset FSGS. Limitations to our study includes the absence of functional characterization to support pathogenicity. Alternatively, identification of additional FSGS cases with suspected deleterious variants in LAMA2 and LOXL4 will provide more evidence for disease causality. Thus, our report will be of benefit to the renal community as sequencing in renal disease becomes more widespread. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12882-021-02524-6. BioMed Central 2021-09-26 /pmc/articles/PMC8474709/ /pubmed/34565340 http://dx.doi.org/10.1186/s12882-021-02524-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Vijayan, Poornima
Hack, Saidah
Yao, Tony
Qureshi, Mohammad Azfar
Paterson, Andrew D.
John, Rohan
Davenport, Bernard
Lennon, Rachel
Pei, York
Barua, Moumita
LAMA2 and LOXL4 are candidate FSGS genes
title LAMA2 and LOXL4 are candidate FSGS genes
title_full LAMA2 and LOXL4 are candidate FSGS genes
title_fullStr LAMA2 and LOXL4 are candidate FSGS genes
title_full_unstemmed LAMA2 and LOXL4 are candidate FSGS genes
title_short LAMA2 and LOXL4 are candidate FSGS genes
title_sort lama2 and loxl4 are candidate fsgs genes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474709/
https://www.ncbi.nlm.nih.gov/pubmed/34565340
http://dx.doi.org/10.1186/s12882-021-02524-6
work_keys_str_mv AT vijayanpoornima lama2andloxl4arecandidatefsgsgenes
AT hacksaidah lama2andloxl4arecandidatefsgsgenes
AT yaotony lama2andloxl4arecandidatefsgsgenes
AT qureshimohammadazfar lama2andloxl4arecandidatefsgsgenes
AT patersonandrewd lama2andloxl4arecandidatefsgsgenes
AT johnrohan lama2andloxl4arecandidatefsgsgenes
AT davenportbernard lama2andloxl4arecandidatefsgsgenes
AT lennonrachel lama2andloxl4arecandidatefsgsgenes
AT peiyork lama2andloxl4arecandidatefsgsgenes
AT baruamoumita lama2andloxl4arecandidatefsgsgenes