LAMA2 and LOXL4 are candidate FSGS genes
Abstract 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 I...
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| Format: | Article |
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BMC
2021-09-01
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| Series: | BMC Nephrology |
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| Online Access: | https://doi.org/10.1186/s12882-021-02524-6 |
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| author | Poornima Vijayan Saidah Hack Tony Yao Mohammad Azfar Qureshi Andrew D. Paterson Rohan John Bernard Davenport Rachel Lennon York Pei Moumita Barua |
| author_facet | Poornima Vijayan Saidah Hack Tony Yao Mohammad Azfar Qureshi Andrew D. Paterson Rohan John Bernard Davenport Rachel Lennon York Pei Moumita Barua |
| author_sort | Poornima Vijayan |
| collection | DOAJ |
| description | Abstract 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. |
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| format | Article |
| id | doaj.art-1baf9a696e0c489a99934778bbd0a795 |
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| issn | 1471-2369 |
| language | English |
| last_indexed | 2024-12-18T01:31:29Z |
| publishDate | 2021-09-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Nephrology |
| spelling | doaj.art-1baf9a696e0c489a99934778bbd0a7952022-12-21T21:25:35ZengBMCBMC Nephrology1471-23692021-09-012211610.1186/s12882-021-02524-6LAMA2 and LOXL4 are candidate FSGS genesPoornima Vijayan0Saidah Hack1Tony Yao2Mohammad Azfar Qureshi3Andrew D. Paterson4Rohan John5Bernard Davenport6Rachel Lennon7York Pei8Moumita Barua9Department of Molecular Genetics, University of TorontoDivision of Nephrology, University Health NetworkDivision of Nephrology, University Health NetworkDivision of Nephrology, University Health NetworkDivision of Epidemiology and Biostatistics, Dalla Lana School of Public HealthDepartment of Laboratory Medicine and Pathology, Toronto General HospitalWellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreWellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreDivision of Nephrology, University Health NetworkDepartment of Molecular Genetics, University of TorontoAbstract 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.https://doi.org/10.1186/s12882-021-02524-6Hereditary FSGSBasement membraneLAMA2LOXL4 |
| spellingShingle | Poornima Vijayan Saidah Hack Tony Yao Mohammad Azfar Qureshi Andrew D. Paterson Rohan John Bernard Davenport Rachel Lennon York Pei Moumita Barua LAMA2 and LOXL4 are candidate FSGS genes BMC Nephrology Hereditary FSGS Basement membrane LAMA2 LOXL4 |
| 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 | Hereditary FSGS Basement membrane LAMA2 LOXL4 |
| url | https://doi.org/10.1186/s12882-021-02524-6 |
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