title: Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome.
abstract: Autosomal recessive Alport syndrome is a progressive hematuric glomerulonephritis characterized by glomerular basement membrane abnormalities and associated with mutations in either the COL4A3 or the COL4A4 gene, which encode the alpha3 and alpha4 type IV collagen chains, respectively. To date, mutation screening in the two genes has been hampered by the lack of genomic structure information. We report here the complete characterization of the 48 exons of the COL4A4 gene, a comprehensive gene screen, and the subsequent detection of 10 novel mutations in eight patients diagnosed with autosomal recessive Alport syndrome. Furthermore, we identified a glycine to alanine substitution in the collagenous domain that is apparently silent in the heterozygous carriers, in 11.5% of all control individuals, and in one control individual homozygous for this glycine substitution. There has been no previous finding of a glycine substitution that is not associated with any obvious phenotype in homozygous individuals.
authors.affiliation: INSERM U423, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Boye
authors.forename: G
authors.initials: G
authors.lastname: Mollet
authors.forename: L
authors.initials: L
authors.lastname: Forestier
authors.forename: L
authors.initials: L
authors.lastname: Cohen-Solal
authors.forename: L
authors.initials: L
authors.lastname: Heidet
authors.forename: P
authors.initials: P
authors.lastname: Cochat
authors.forename: J P
authors.initials: JP
authors.lastname: Grünfeld
authors.forename: J B
authors.initials: JB
authors.lastname: Palcoux
authors.forename: M C
authors.initials: MC
authors.lastname: Gubler
authors.forename: C
authors.initials: C
authors.lastname: Antignac
mesh_terms: D000409:Alanine; D019943:Amino Acid Substitution; D001483:Base Sequence; D001485:Basement Membrane / Q000002:abnormalities; D003094:Collagen / Q000235:genetics*; D017931:DNA Primers; D005091:Exons; D005260:Female; D005808:Genes, Recessive; D006580:Genetic Carrier Screening; D005998:Glycine; D006720:Homozygote; D006801:Humans; D007438:Introns; D007678:Kidney Glomerulus / Q000002:abnormalities; D046911:Macromolecular Substances; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009394:Nephritis, Hereditary / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000235:genetics
chemical_list: D017931:DNA Primers; D046911:Macromolecular Substances; D020033:Protein Isoforms; D003094:Collagen; D000409:Alanine; D005998:Glycine