Co-Inheritance of Functional Podocin Variants with Heterozygous Collagen IV Mutations Predisposes to Renal Failure
| Autor: | Stefanou, Charalambos, Pieri, Myrtani, Savva, Isavella, Georgiou, Georgios C., Pierides, Alkis M., Voskarides, Konstantinos, Constantinou-Deltas, Constantinos D. |
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| Přispěvatelé: | Constantinou-Deltas, Constantinos D. [0000-0001-5549-9169] |
| Rok vydání: | 2015 |
| Předmět: |
Male
urologic and male genital diseases Autoantigens Cohort Studies Focal segmental glomerulosclerosis middle aged Glomerular Basement Membrane genetics membrane protein Proteinuria biology Glomerulosclerosis Focal Segmental Glomerular basement membrane disease course allele Intracellular Signaling Peptides and Proteins pedigree Middle Aged cohort analysis female genital diseases and pregnancy complications autoantigen Pedigree aged medicine.anatomical_structure female Disease Progression Female medicine.symptom focal glomerulosclerosis Collagen Type IV medicine.medical_specialty Heterozygote sex difference Inheritance (object-oriented programming) Sex Factors male collagen type 4 Internal medicine medicine Humans signal peptide human Alleles Aged business.industry urogenital system Membrane Proteins medicine.disease type IV collagen alpha3 chain heterozygote Endocrinology Mutation Podocin biology.protein glomerulus basement membrane Kidney Failure Chronic pathology proteinuria mutation business podocin |
| Zdroj: | Nephron |
| ISSN: | 2235-3186 |
| Popis: | Background/Aims: A subset of patients who present with proteinuria and are diagnosed with focal segmental glomerulosclerosis (FSGS) have inherited heterozygous COL4A3/A4 mutations and are also diagnosed with thin basement membrane nephropathy (TBMN-OMIM: 141200). Two studies showed that co-inheritance of NPHS2-p.Arg229Gln, a podocin variant, may increase the risk for proteinuria and renal function decline. Methods: We hypothesized that additional podocin variants may exert a similar effect. We studied genetically a well-characterized Cypriot TBMN patient cohort by re-sequencing the NPHS2 coding region. We also performed functional studies in cell culture experiments, investigating the interaction of podocin variants with itself and with nephrin. Results: Potentially disease-modifying podocin variants were searched for by analyzing NPHS2 in 35 ‘severe' TBMN patients. One non-synonymous variant, p.Glu237Gln, was detected. Both variants, p.Arg229Gln and p.Glu237Gln, were tested in a larger cohort of 122 TBMN patients, who were categorized as ‘mild' or ‘severe' based on the presence of microscopic hematuria alone or combined with chronic renal failure and/or proteinuria. Seven ‘severe' patients carried either of the 2 variants; none was present in the ‘mild' patients (p = 0.05, Pearson χ2). The 7 carriers belong in 2 families segregating mutation COL4A3-p.Gly1334Glu. Inheritance of the wild-type (WT) and mutant alleles correlated with the phenotype (combined concordance probability 0.003). Immunofluorescence (IF) experiments after dual co-transfection of WT and mutant podocin suggested altered co-localization of mutant homodimers. IF experiments after co-transfection of WT podocin and nephrin showed normal membrane localization, while both podocin variants interfered with normal trafficking, demonstrating perinuclear staining. Immunoprecipitation experiments showed stronger binding of mutant podocin to WT podocin or nephrin. Conclusion: The results support the hypothesis that certain hypomorphic podocin variants may act as adverse genetic modifiers when co-inherited with COL4A3/A4 mutations, thus predisposing to FSGS and severe kidney function decline. |
| Databáze: | OpenAIRE |
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