title: A novel COL4A1 frameshift mutation in familial kidney disease: the importance of the C-terminal NC1 domain of type IV collagen.
abstract: Hereditary microscopic haematuria often segregates with mutations of COL4A3, COL4A4 or COL4A5 but in half of families a gene is not identified. We investigated a Cypriot family with autosomal dominant microscopic haematuria with renal failure and kidney cysts.
  
  
  
  We used genome-wide linkage analysis, whole exome sequencing and cosegregation analyses.
  
  
  
  We identified a novel frameshift mutation, c.4611_4612insG:p.T1537fs, in exon 49 of COL4A1. This mutation predicts truncation of the protein with disruption of the C-terminal part of the NC1 domain. We confirmed its presence in 20 family members, 17 with confirmed haematuria, 5 of whom also had stage 4 or 5 chronic kidney disease. Eleven family members exhibited kidney cysts (55% of those with the mutation), but muscle cramps or cerebral aneurysms were not observed and serum creatine kinase was normal in all individuals tested.
  
  
  
  Missense mutations of COL4A1 that encode the CB3 [IV] segment of the triple helical domain (exons 24 and 25) are associated with HANAC syndrome (hereditary angiopathy, nephropathy, aneurysms and cramps). Missense mutations of COL4A1 that disrupt the NC1 domain are associated with antenatal cerebral haemorrhage and porencephaly, but not kidney disease. Our findings extend the spectrum of COL4A1 mutations linked with renal disease and demonstrate that the highly conserved C-terminal part of the NC1 domain of the α1 chain of type IV collagen is important in the integrity of glomerular basement membrane in humans.
authors.affiliation: UCL Centre for Nephrology, University College, London, UK.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Gale
authors.affiliation: Nephrology Department, Nicosia State Hospital, Nicosia, North Cyprus.
authors.forename: D Deren
authors.initials: DD
authors.lastname: Oygar
authors.affiliation: UCL Centre for Nephrology, University College, London, UK.|Department of Nephrology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Fujun
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, Nicosia State Hospital, Nicosia, North Cyprus.
authors.forename: P Derin
authors.initials: PD
authors.lastname: Oygar
authors.affiliation: UCL Centre for Nephrology, University College, London, UK.
authors.forename: Nadia
authors.initials: N
authors.lastname: Khan
authors.affiliation: West London Renal and Transplant Institute, Imperial College, London, UK.
authors.forename: Thomas M F
authors.initials: TM
authors.lastname: Connor
authors.affiliation: South West Thames Institute for Renal Research, St Helier Hospital, Carshalton, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Lapsley
authors.affiliation: School of Clinical Medicine, Cambridge University, Cambridge, UK.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.affiliation: UCL Centre for Nephrology, University College, London, UK.
authors.forename: Guy H
authors.initials: GH
authors.lastname: Neild
mesh_terms: D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D009394:Nephritis, Hereditary / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D016133:Polymerase Chain Reaction
chemical_list: C547475:COL4A1 protein, human; D024141:Collagen Type IV; D004247:DNA
keywords: COL4A1; familial nephropathy; genetic renal disease; glomerular basement membrane; type IV collagen