title: A novel Cys1638Tyr NC1 domain substitution in alpha5(IV) collagen causes Alport syndrome with late onset renal failure without hearing loss or eye abnormalities.
abstract: BACKGROUND
  Mutations in the type IV collagen gene, COL4A5, are associated with Alport syndrome, characterized by ultrastructural abnormalities of the glomerular basement membrane (GBM), with or without progressive loss of renal function, characteristic ophthalmic signs and/or high tone sensorineural deafness. More than 300 sequence variants in type IV collagen have been identified, including alterations in the non-collagenous NC1 domain.
  
  
  METHODS
  We performed linkage analysis and sequencing to identify the mutation in a New Zealand family with Alport glomerulonephritis and late onset renal failure without hearing loss or eye abnormalities.
  
  
  RESULTS
  We report a novel c.4913G>A (p.Cys1638Tyr) alteration in the NC1 domain of COL4A5, identified in a moderately large family, eight of whom were confirmed by renal biopsy to have renal abnormalities. Only three of eight mutant male members of the pedigree progressed to end-stage renal failure. The remaining five mutant males exhibit either chronic renal disease at age 36, 46 and 72, or as yet show no renal disease at ages 39 and 39. Extra-renal manifestations such as sensorineural deafness or ocular changes were absent from all family members carrying the mutation.
  
  
  CONCLUSIONS
  This variant is the first reported to affect the tenth of 12 cysteine residues in the NC1 domain. We conclude that the cysteine to tyrosine substitution in the NC1 domain of the alpha5(IV) collagen chain in this family leads to a mild form of Alport syndrome, including absence of extra-renal features.
authors.affiliation: Department of Pathology, University of Otago, P.O. Box 913, Dunedin, New Zealand.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Wilson
authors.forename: Han-Seung
authors.initials: HS
authors.lastname: Yoon
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Walker
authors.forename: Michael R
authors.initials: MR
authors.lastname: Eccles
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D024141:Collagen Type IV / Q000235:genetics*; D003545:Cysteine; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D050533:Glomerular Basement Membrane / Q000002:abnormalities; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009394:Nephritis, Hereditary / Q000235:genetics*; D009520:New Zealand; D010375:Pedigree; D051437:Renal Insufficiency / Q000235:genetics*; D014443:Tyrosine
chemical_list: C478159:COL4A5 protein, human; D024141:Collagen Type IV; D014443:Tyrosine; D003545:Cysteine