Frequency of COL4A3/COL4A4 Mutations amongst families segregating glomerular microscopic hematuria and evidence for activation of the unfolded protein response. Focal and segmental glomerulosclerosis is a frequent development during ageing

Louiza Papazachariou, Panayiota Demosthenous, Myrtani Pieri, Gregory Papagregoriou, Isavella Savva, Christoforos Stavrou, Michael Zavros, Yiannis Athanasiou, Kyriakos Ioannou, Charalambos Patsias, Alexia Panagides, Costas Potamitis, Kyproula Demetriou, Marios Prikis, Michael Hadjigavriel, Maria Kkolou, Panayiota Loukaidou, Androulla Pastelli, Aristos Michael, Akis LazarouMaria Arsali, Loukas Damianou, Ioanna Goutziamani, Andreas Soloukides, Lakis Yioukas, Avraam Elia, Ioanna Zouvani, Polycarpos Polycarpou, Alkis Pierides, Konstantinos Voskarides, Constantinos Deltas

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)

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.

Original languageEnglish
Article numbere115015
JournalPLoS ONE
Volume9
Issue number12
DOIs
Publication statusPublished - 16 Dec 2014

Fingerprint

Dive into the research topics of 'Frequency of COL4A3/COL4A4 Mutations amongst families segregating glomerular microscopic hematuria and evidence for activation of the unfolded protein response. Focal and segmental glomerulosclerosis is a frequent development during ageing'. Together they form a unique fingerprint.

Cite this