title: Novel X-linked glomerulopathy is associated with a COL4A5 missense mutation in a non-collagenous interruption.
abstract: A novel COL4A5 mutation causes rapid progression to end-stage renal disease in males, despite the absence of clinical and biopsy findings associated with Alport syndrome. Affected males have proteinuria, variable hematuria, and an early progression to end-stage renal disease. Renal biopsy findings include global and segmental glomerulosclerosis, mesangial hypercellularity and basement membrane immune complex deposition. Exon sequencing of the COL4A5 locus identified a thymine to guanine transversion at nucleotide 665, resulting in a phenylalanine to cysteine missense mutation at codon 222. The phenylalanine at position 222 is absolutely conserved among vertebrates. This mutation was confirmed in 4 affected males and 4 female obligate carriers, but was absent in 6 asymptomatic male family members and 198 unrelated individuals. Immunostaining for α5(IV) collagen in renal biopsies from affected males was normal. This mutation, in a non-collagenous interruption associated with severe renal disease, provides evidence for the importance of this structural motif and suggests the range of phenotypes associated with COL4A5 mutations is more diverse than previously realized. Hence, COL4A5 mutation analysis should be considered when glomerulonephritis presents in an X-linked inheritance pattern, even with a presentation distinct from Alport syndrome.
authors.affiliation: Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43205, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Becknell
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Zender
authors.forename: Ronald
authors.initials: R
authors.lastname: Houston
authors.forename: Peter B
authors.initials: PB
authors.lastname: Baker
authors.forename: Kim L
authors.initials: KL
authors.lastname: McBride
authors.forename: Wentian
authors.initials: W
authors.lastname: Luo
authors.forename: David S
authors.initials: DS
authors.lastname: Hains
authors.forename: Dorin-Bogdan
authors.initials: DB
authors.lastname: Borza
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Schwaderer
mesh_terms: D000293:Adolescent; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics*; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D005260:Female; D050533:Glomerular Basement Membrane / Q000473:pathology*; D005921:Glomerulonephritis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: C478159:COL4A5 protein, human; D024141:Collagen Type IV