title: Substitution of arginine for glycine 325 in the collagen alpha 5 (IV) chain associated with X-linked Alport syndrome: characterization of the mutation by direct sequencing of PCR-amplified lymphoblast cDNA fragments.
abstract: A large kindred with adult-type X-linked Alport syndrome was studied with regard to a defect in the recently described COL4A5 collagen gene. Southern blot analysis with COL4A5 cDNA probes showed loss of a MspI restriction site. Direct sequencing of cDNA amplified from lymphoblast mRNA demonstrated a single-base substitution converting a glycine codon to arginine at position 325 in the alpha 5 chain of type IV collagen. The triple-helical collagenous domain of alpha 5(IV), characterized by a Gly-X-Y repeat sequence, is interrupted 22 times by noncollagenous sequences. The mutation creates an additional interruption in the Gly-X-Y repeat motif, between interruptions 4 and 5. It is interesting that such glycine substitutions inside the COL1A1 or COL1A2 genes have been associated with many cases of osteogenesis imperfecta. This gly325-to-arg substitution presumably alters the triple-helix formation, and, in turn, modifies the ultrastructural and functional characteristics of the type IV collagen network inside the glomerular basement membrane.
authors.affiliation: INSERM Unité 192, Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Knebelmann
authors.forename: G
authors.initials: G
authors.lastname: Deschenes
authors.forename: F
authors.initials: F
authors.lastname: Gros
authors.forename: M C
authors.initials: MC
authors.lastname: Hors
authors.forename: J P
authors.initials: JP
authors.lastname: Grünfeld
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.forename: K
authors.initials: K
authors.lastname: Tryggvason
authors.forename: M C
authors.initials: MC
authors.lastname: Gubler
authors.forename: C
authors.initials: C
authors.lastname: Antignac
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001120:Arginine; D001483:Base Sequence; D003094:Collagen / Q000737:chemistry* / Q000235:genetics; D019003:Deoxyribonuclease HpaII; D015252:Deoxyribonucleases, Type II Site-Specific; D005260:Female; D015723:Gene Library; D008040:Genetic Linkage; D005998:Glycine; D006801:Humans; D008214:Lymphocytes; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009394:Nephritis, Hereditary / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D014960:X Chromosome
chemical_list: D003094:Collagen; D001120:Arginine; D019003:Deoxyribonuclease HpaII; D015252:Deoxyribonucleases, Type II Site-Specific; D005998:Glycine