title: 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.
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.
authors.affiliation: Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, University of Cyprus, Nicosia, Cyprus.
authors.forename: Louiza
authors.initials: L
authors.lastname: Papazachariou
authors.affiliation: Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, University of Cyprus, Nicosia, Cyprus.
authors.forename: Panayiota
authors.initials: P
authors.lastname: Demosthenous
authors.affiliation: Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, University of Cyprus, Nicosia, Cyprus.
authors.forename: Myrtani
authors.initials: M
authors.lastname: Pieri
authors.affiliation: Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, University of Cyprus, Nicosia, Cyprus.
authors.forename: Gregory
authors.initials: G
authors.lastname: Papagregoriou
authors.affiliation: Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, University of Cyprus, Nicosia, Cyprus.
authors.forename: Isavella
authors.initials: I
authors.lastname: Savva
authors.affiliation: Department of Nephrology, Evangelismos Hospital, Pafos, Cyprus.
authors.forename: Christoforos
authors.initials: C
authors.lastname: Stavrou
authors.affiliation: Department of Nephrology, Nicosia General Hospital, Nicosia, Cyprus.
authors.forename: Michael
authors.initials: M
authors.lastname: Zavros
authors.affiliation: Department of Nephrology, Nicosia General Hospital, Nicosia, Cyprus.
authors.forename: Yiannis
authors.initials: Y
authors.lastname: Athanasiou
authors.affiliation: Department of Nephrology, Nicosia General Hospital, Nicosia, Cyprus.
authors.forename: Kyriakos
authors.initials: K
authors.lastname: Ioannou
authors.affiliation: Department of Nephrology, Nicosia General Hospital, Nicosia, Cyprus.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Patsias
authors.affiliation: Department of Nephrology, Nicosia General Hospital, Nicosia, Cyprus.
authors.forename: Alexia
authors.initials: A
authors.lastname: Panagides
authors.affiliation: Department of Nephrology, Nicosia General Hospital, Nicosia, Cyprus.
authors.forename: Costas
authors.initials: C
authors.lastname: Potamitis
authors.affiliation: Department of Nephrology, Nicosia General Hospital, Nicosia, Cyprus.
authors.forename: Kyproula
authors.initials: K
authors.lastname: Demetriou
authors.affiliation: Department of Nephrology, Nicosia General Hospital, Nicosia, Cyprus.
authors.forename: Marios
authors.initials: M
authors.lastname: Prikis
authors.affiliation: Department of Nephrology, Larnaca General Hospital, Larnaca, Cyprus.
authors.forename: Michael
authors.initials: M
authors.lastname: Hadjigavriel
authors.affiliation: Department of Nephrology, Larnaca General Hospital, Larnaca, Cyprus.
authors.forename: Maria
authors.initials: M
authors.lastname: Kkolou
authors.affiliation: Department of Nephrology, Larnaca General Hospital, Larnaca, Cyprus.
authors.forename: Panayiota
authors.initials: P
authors.lastname: Loukaidou
authors.affiliation: Department of Nephrology, Larnaca General Hospital, Larnaca, Cyprus.
authors.forename: Androulla
authors.initials: A
authors.lastname: Pastelli
authors.affiliation: Department of Nephrology, Limassol General Hospital, Limassol, Cyprus.
authors.forename: Aristos
authors.initials: A
authors.lastname: Michael
authors.affiliation: Department of Nephrology, Limassol General Hospital, Limassol, Cyprus.
authors.forename: Akis
authors.initials: A
authors.lastname: Lazarou
authors.affiliation: Department of Nephrology, Limassol General Hospital, Limassol, Cyprus.
authors.forename: Maria
authors.initials: M
authors.lastname: Arsali
authors.affiliation: Department of Nephrology, Limassol General Hospital, Limassol, Cyprus.
authors.forename: Loukas
authors.initials: L
authors.lastname: Damianou
authors.affiliation: Department of Nephrology, Limassol General Hospital, Limassol, Cyprus.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Goutziamani
authors.affiliation: Department of Nephrology, Limassol General Hospital, Limassol, Cyprus.
authors.forename: Andreas
authors.initials: A
authors.lastname: Soloukides
authors.affiliation: Department of Nephrology, Paphos General Hospital, Paphos, Cyprus.
authors.forename: Lakis
authors.initials: L
authors.lastname: Yioukas
authors.affiliation: Department of Pediatrics, Archbishop Makarios III Hospital, Nicosia, Cyprus.
authors.forename: Avraam
authors.initials: A
authors.lastname: Elia
authors.affiliation: Department of Histopathology, Nicosia General Hospital, Nicosia, Cyprus.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Zouvani
authors.affiliation: Department of Nephrology, Apollonion Private Hospital, Nicosia, Cyprus.
authors.forename: Polycarpos
authors.initials: P
authors.lastname: Polycarpou
authors.affiliation: Department of Nephrology, Hippocrateon Hospital, Nicosia, Cyprus.
authors.forename: Alkis
authors.initials: A
authors.lastname: Pierides
authors.affiliation: Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, University of Cyprus, Nicosia, Cyprus.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Voskarides
authors.affiliation: Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, University of Cyprus, Nicosia, Cyprus.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Deltas
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging; D001324:Autoantigens / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D024141:Collagen Type IV / Q000235:genetics*; D005260:Female; D050533:Glomerular Basement Membrane / Q000473:pathology*; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D006417:Hematuria / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009394:Nephritis, Hereditary / Q000235:genetics; D050199:Podocytes / Q000378:metabolism; D017422:Sequence Analysis, DNA; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D001324:Autoantigens; C466620:COL4A4 protein, human; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain