title: X-linked Alport syndrome: an SSCP-based mutation survey over all 51 exons of the COL4A5 gene.
abstract: The COL4A5 gene encodes the alpha5 (type IV) collagen chain and is defective in X-linked Alport syndrome (AS). Here, we report the first systematic analysis of all 51 exons of COL4A5 gene in a series of 201 Italian AS patients. We have previously reported nine major rearrangements, as well as 18 small mutations identified in the same patient series by SSCP analysis of several exons. After systematic analysis of all 51 exons of COL4A5, we have now identified 30 different mutations: 10 glycine substitutions in the triple helical domain of the protein, 9 frameshift mutations, 4 in-frame deletions, 1 start codon, 1 nonsense, and 5 splice-site mutations. These mutations were either unique or found in two unrelated families, thus excluding the presence of a common mutation in the coding part of the gene. Overall, mutations were detected in only 45% of individuals with a certain or likely diagnosis of X-linked AS. This finding suggests that mutations in noncoding segments of COL4A5 account for a high number of X-linked AS cases. An alternative hypothesis is the presence of locus heterogeneity, even within the X-linked form of the disease. A genotype/phenotype comparison enabled us to better substantiate a significant correlation between the degree of predicted disruption of the alpha5 chain and the severity of phenotype in affected male individuals. Our study has significant implications in the diagnosis and follow-up of AS patients.
authors.affiliation: Medical Genetics, Department of Molecular Biology, Policlinico Le Scotte, Siena, Italy. ballabio@unisi.it
authors.forename: A
authors.initials: A
authors.lastname: Renieri
authors.forename: M
authors.initials: M
authors.lastname: Bruttini
authors.forename: L
authors.initials: L
authors.lastname: Galli
authors.forename: P
authors.initials: P
authors.lastname: Zanelli
authors.forename: T
authors.initials: T
authors.lastname: Neri
authors.forename: S
authors.initials: S
authors.lastname: Rossetti
authors.forename: A
authors.initials: A
authors.lastname: Turco
authors.forename: N
authors.initials: N
authors.lastname: Heiskari
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.forename: R
authors.initials: R
authors.lastname: Gusmano
authors.forename: L
authors.initials: L
authors.lastname: Massella
authors.forename: G
authors.initials: G
authors.lastname: Banfi
authors.forename: F
authors.initials: F
authors.lastname: Scolari
authors.forename: A
authors.initials: A
authors.lastname: Sessa
authors.forename: G
authors.initials: G
authors.lastname: Rizzoni
authors.forename: K
authors.initials: K
authors.lastname: Tryggvason
authors.forename: P F
authors.initials: PF
authors.lastname: Pignatti
authors.forename: M
authors.initials: M
authors.lastname: Savi
authors.forename: A
authors.initials: A
authors.lastname: Ballabio
authors.forename: M
authors.initials: M
authors.lastname: De Marchi
mesh_terms: D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D001483:Base Sequence; D003062:Codon; D003094:Collagen / Q000235:genetics*; D017931:DNA Primers; D004251:DNA Transposable Elements; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D015321:Gene Rearrangement; D005998:Glycine; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics; D046911:Macromolecular Substances; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009394:Nephritis, Hereditary / Q000235:genetics*; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011487:Protein Conformation; D017384:Sequence Deletion; D014960:X Chromosome
chemical_list: D003062:Codon; D017931:DNA Primers; D004251:DNA Transposable Elements; D046911:Macromolecular Substances; D003094:Collagen; D005998:Glycine