title: Autosomal dominant Alport syndrome caused by a COL4A3 splice site mutation.
abstract: BACKGROUND
  Alport syndrome (AS) is a clinically and genetically heterogeneous renal disorder, predominantly affecting the type IV collagen alpha 3/alpha 4/alpha 5 network of the glomerular basement membrane (GBM). AS can be caused by mutations in any of the three genes encoding these type IV collagen chains. The majority of AS families (85%) are X-linked (XL-AS) involving mutations in the COL4A5 gene. Mutations in the COL4A3 and COL4A4 genes cause autosomal recessive AS (AR-AS), accounting for approximately 14% of the cases. Recently, autosomal dominant AS (AD-AS) was linked to the COL4A3/COL4A4 locus in a large family.
  
  
  METHODS
  COL4A3 and COL4A4 cDNAs were generated by nested reverse transcription-polymerase chain reaction and were analyzed by DNA sequence analysis. Denaturating high-performance liquid chromatography (DHPLC) was used for mutation and segregation analysis at the genomic DNA level.
  
  
  RESULTS
  In the AD-AS family, a splice site mutation resulting in skipping of exon 21 of the COL4A3 gene was detected. The mutation does not alter the reading frame and is predicted to result in a COL4A3 chain with an internal deletion.
  
  
  CONCLUSIONS
  As the NC domain is intact, this chain may be incorporated and distort the collagen triple helix, thereby causing the dominant effect of the mutation. The finding of a specific COL4A3 mutation in AD-AS completes the spectrum of type IV collagen mutations in all genetic forms of AS.
authors.affiliation: Department of Molecular Cell Biology and Genetics, Maastricht University, Maastricht, The Netherlands.
authors.forename: F T
authors.initials: FT
authors.lastname: van der Loop
authors.forename: L
authors.initials: L
authors.lastname: Heidet
authors.forename: E D
authors.initials: ED
authors.lastname: Timmer
authors.forename: B J
authors.initials: BJ
authors.lastname: van den Bosch
authors.forename: A
authors.initials: A
authors.lastname: Leinonen
authors.forename: C
authors.initials: C
authors.lastname: Antignac
authors.forename: J A
authors.initials: JA
authors.lastname: Jefferson
authors.forename: A P
authors.initials: AP
authors.lastname: Maxwell
authors.forename: L A
authors.initials: LA
authors.lastname: Monnens
authors.forename: C H
authors.initials: CH
authors.lastname: Schröder
authors.forename: H J
authors.initials: HJ
authors.lastname: Smeets
mesh_terms: D000328:Adult; D001483:Base Sequence / Q000235:genetics; D003094:Collagen / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D004274:DNA, Recombinant; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D009154:Mutation; D009394:Nephritis, Hereditary / Q000235:genetics*; D009692:Nucleic Acid Heteroduplexes; D010375:Pedigree
chemical_list: D018076:DNA, Complementary; D004274:DNA, Recombinant; D009692:Nucleic Acid Heteroduplexes; D003094:Collagen