COL4A5 and LAMA5 variants co-inherited in familial hematuria: Digenic inheritance or genetic modifier effect?
| Autor: | Voskarides, Konstantinos, Papagregoriou, Gregory, Hadjipanagi, Despina, Petrou, Ioanelli, Savva, Isavella, Elia, Avraam, Athanasiou, Yiannis, Pastelli, Androulla, Kkolou, Maria, Hadjigavriel, Michalis, Stavrou, Christoforos, Pierides, Alkis, Deltas, Constantinos |
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| Přispěvatelé: | Deltas, Constantinos [0000-0001-5549-9169] |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Pathology 030232 urology & nephrology Renal cysts lcsh:RC870-923 urologic and male genital diseases Glomerulonephritis Membranous 0302 clinical medicine Focal segmental glomerulosclerosis Medicine Exome sequencing Metalloproteinase Collagen IV Glomerular basement membrane Middle Aged Kidney disease female genital diseases and pregnancy complications Pedigree medicine.anatomical_structure Nephrology Laminin alpha 5 Female medicine.symptom Research Article Adult Collagen Type IV medicine.medical_specialty Kidney cysts Nephropathy 03 medical and health sciences Internal medicine Exome Sequencing Humans Digenic inheritance Genetic Testing Alport syndrome Hematuria Modifier gene business.industry Genetic Variation Familial hematuria medicine.disease lcsh:Diseases of the genitourinary system. Urology FSGS 030104 developmental biology Thin Basement Membrane Nephropathy (TBMN) Synaptopodin Laminin business |
| Zdroj: | BMC Nephrology, Vol 19, Iss 1, Pp 1-8 (2018) BMC Nephrology |
| DOI: | 10.1186/s12882-018-0906-5 |
| Popis: | Background: About 40-50% of patients with familial microscopic hematuria (FMH) caused by thin basement membrane nephropathy (TBMN) inherit heterozygous mutations in collagen IV genes (COL4A3, COL4A4). On long follow-up, the full phenotypic spectrum of these patients varies a lot, ranging from isolated MH or MH plus low-grade proteinuria to chronic renal failure of variable degree, including end-stage renal disease (ESRD). Methods: Here, we performed Whole Exome Sequencing (WES) in patients of six families, presenting with autosomal dominant FMH, with or without progression to proteinuria and loss of renal function, all previously found negative for severe collagen IV mutations. Hierarchical filtering of the WES data was performed, followed by mutation prediction analysis, Sanger sequencing and genetic segregation analysis. Results: In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-p.Pro1243Leu and COL4A5-p.Asp654Tyr. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts. Conclusions: A modifier role of LAMA5 on the background of a hypomorphic Alport syndrome causing mutation is a possible explanation of our findings. Digenic inheritance is another scenario, following the concept that mutations at both loci more accurately explain the spectrum of symptoms, but further investigation is needed under this concept. This is the third report linking a LAMA5 variant with human renal disease and expanding the spectrum of genes involved in glomerular pathologies accompanied by familial hematurias. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced Lama5 protein levels and produced kidney cysts. 2018 The Author(s). The work was supported from the Cyprus Research Promotion Foundation through the grant NEW INFRASTRUCTURE/STRATEGIC/0308/24 to CD (co-funded by the European Regional Development Fund and the Republic of Cyprus). The funding body did not contribute to the design of study, collection, analysis and interpretation of data, or in manuscript writing. Scopus |
| Databáze: | OpenAIRE |
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