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
Ημερομηνία
2014Συγγραφέας
Papazachariou, LouizaDemosthenous, Panayiota
Pieri, Myrtani
Papagregoriou, Gregory N.
Savva, Isavella
Stavrou, Christoforos V.
Zavros, Michalis
Athanasiou, Yiannis
Ioannou, Kyriakos
Patsias, Charalambos
Panagides, Alexia
Potamitis, Costas
Demetriou, Kyproula
Prikis, Marios
Hadjigavriel, Michalis
Kkolou, Maria
Loukaidou, Panayiota
Pastelli, Androulla
Michael, Aristos
Lazarou, Akis
Arsali, Maria
Damianou, Loukas
Goutziamani, Ioanna
Soloukides, Andreas P.
Yioukas, Lakis
Elia, Avraam
Zouvani, Ioanna
Polycarpou, Polycarpos
Pierides, Alkis M.
Voskarides, Konstantinos
Constantinou-Deltas, Constantinos D.
ISSN
1932-6203Source
PLoS ONEVolume
9Google Scholar check
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Εμφάνιση πλήρους εγγραφήςΕπιτομή
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. © 2014 Papazachariou et al.
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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
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