Abstract
Familial glomerular hematuria(s) comprise a genetically heterogeneous group of conditions which include Alport Syndrome (AS) and thin basement membrane nephropathy (TBMN). Here we investigated 57 Greek-Cypriot families presenting glomerular microscopic hematuria (GMH), with or without proteinuria or chronic kidney function decline, but excluded classical AS. We specifically searched the COL4A3/A4 genes and identified 8 heterozygous mutations in 16 families (28,1%). Eight non-related families featured the founder mutation COL4A3-p.(G1334E). Renal biopsies from 8 patients showed TBMN and focal segmental glomerulosclerosis (FSGS). Ten patients (11.5%) reached end-stage kidney disease (ESKD) at ages ranging from 37-69-yo (mean 50,1-yo). Next generation sequencing of the patients who progressed to ESKD failed to reveal a second mutation in any of the COL4A3/A4/A5 genes, supporting that true heterozygosity for COL4A3/A4 mutations predisposes to CRF/ESKD. Although this could be viewed as a milder and late-onset form of autosomal dominant AS, we had no evidence of ultrastructural features or extrarenal manifestations that would justify this diagnosis. Functional studies in cultured podocytes transfected with wild type or mutant COL4A3 chains showed retention of mutant collagens and differential activation of the unfolded protein response (UPR) cascade. This signifies the potential role of the UPR cascade in modulating the final phenotype in patients with collagen IV nephropathies.
Highlights
During the last three decades, progress in molecular genetics has allowed better investigation and understanding of patients with familial microscopic hematuria (FMH) of glomerular origin
Our findings substantiate the observation that familial MH in about 40% of cases is caused by heterozygous COL4A3/A4 mutations, while it is more than certain that additional still unknown genes exist that are responsible for a similar phenotype
As the DNA analysis technology is improving and Next Generation Sequencing (NGS) approaches are becoming routine practice, more experts may prefer to use genetic testing as a first-tier approach for diagnosis, before they resolve to an invasive method such as a skin or a renal biopsy [53]
Summary
During the last three decades, progress in molecular genetics has allowed better investigation and understanding of patients with familial microscopic hematuria (FMH) of glomerular origin. Mutations in COL4A3/A4/A5, coding for the alpha chains of the trimeric collagen IV, the most important structural component of the glomerular basement membrane (GBM) [2, 3] appear to be responsible for the two most frequent causes of FMH These are thin basement membrane nephropathy (TBMN) and Alport Syndrome (AS) [4, 5]. In many families carrying such mutations, some members continue to exhibit pure and isolated MH for the rest of their lives, while others develop proteinuria later on in life, usually with hypertension and a variable gradual progression to CRF, up to ESKD [6,7,8] This phenotypic heterogeneity raises several aetiologic questions and has great clinical relevance
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