title: COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy.
abstract: Mutations in the COL4A3/COL4A4 genes of type IV collagen have been found in approximately 40% of cases of thin basement membrane nephropathy, which is characterized by microscopic hematuria and is classically thought to cause proteinuria and chronic renal failure rarely. Here we report our observations of 116 subjects from 13 Cypriot families clinically affected with thin basement membrane nephropathy. These families first came to our attention because they segregated microscopic hematuria, mild proteinuria, and variable degrees of renal impairment, but a dual diagnosis of focal segmental glomerulosclerosis (FSGS) and thin basement membrane nephropathy was made in 20 biopsied cases. Molecular studies identified founder mutations in both COL4A3 and COL4A4 genes in 10 families. None of 82 heterozygous patients had any extrarenal manifestations, supporting the diagnosis of thin basement membrane nephropathy. During follow-up of up to three decades, 31 of these 82 patients (37.8%) developed chronic renal failure and 16 (19.5%) reached end-stage renal disease. Mutations G1334E and G871C were detected in seven and three families, respectively, and were probably introduced by founders. We conclude that these particular COL4A3/COL4A4 mutations either predispose some patients to FSGS and chronic renal failure, or that thin basement membrane nephropathy sometimes coexists with another genetic modifier that is responsible for FSGS and progressive renal failure. The findings presented here do not justify the labelling of thin basement membrane nephropathy as a benign condition with excellent prognosis.
authors.affiliation: Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Voskarides
authors.forename: Loukas
authors.initials: L
authors.lastname: Damianou
authors.forename: Vassos
authors.initials: V
authors.lastname: Neocleous
authors.forename: Ioanna
authors.initials: I
authors.lastname: Zouvani
authors.forename: Stalo
authors.initials: S
authors.lastname: Christodoulidou
authors.forename: Valsamakis
authors.initials: V
authors.lastname: Hadjiconstantinou
authors.forename: Kyriacos
authors.initials: K
authors.lastname: Ioannou
authors.forename: Yiannis
authors.initials: Y
authors.lastname: Athanasiou
authors.forename: Charalampos
authors.initials: C
authors.lastname: Patsias
authors.forename: Efstathios
authors.initials: E
authors.lastname: Alexopoulos
authors.forename: Alkis
authors.initials: A
authors.lastname: Pierides
authors.forename: Kyriacos
authors.initials: K
authors.lastname: Kyriacou
authors.forename: Constantinos
authors.initials: C
authors.lastname: Deltas
mesh_terms: D000328:Adult; D001324:Autoantigens / Q000235:genetics*; D015331:Cohort Studies; D024141:Collagen Type IV / Q000235:genetics*; D003535:Cyprus; D005260:Female; D018703:Founder Effect; D008040:Genetic Linkage / Q000235:genetics; D050533:Glomerular Basement Membrane / Q000473:pathology*; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology; D006417:Hematuria / Q000235:genetics / Q000473:pathology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree
chemical_list: D001324:Autoantigens; C466620:COL4A4 protein, human; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain