title: COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome.
abstract: COL4A3/COL4A4 mutations: From familial hematuria to autosomal-dominant or recessive Alport syndrome.
  
  
  BACKGROUND
  Mutations of the type IV collagen COL4A5 gene cause X-linked Alport syndrome (ATS). Mutations of COL4A3 and COL4A4 have been reported both in autosomal-recessive and autosomal-dominant ATS, as well as in benign familial hematuria (BFH). In the latter conditions, however, clinical features are less defined, few mutations have been reported, and other genes and non-genetic factors may be involved.
  
  
  METHODS
  We analyzed 36 ATS patients for COL4A3 and COL4A4 mutations by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and direct sequencing. Sporadic patients who had tested negative for COL4A5 mutations were included with typical cases of autosomal recessive ATS to secure a better definition of the phenotype spectrum.
  
  
  RESULTS
  We identified seven previously undescribed COL4A3 mutations: in two genetic compounds and three heterozygotes, and one in COL4A4. In agreement with the literature, some of the mutations of compound heterozygotes were associated with microhematuria in healthy heterozygous relatives. The mutations of heterozygous patients are likely dominant, since no change was identified in the second allele even by sequencing, and they are predicted to result in shortened or abnormal chains with a possible dominant-negative effect. In addition, both genes showed rare variants of unclear pathogenicity, and common polymorphisms that are shared in part with other populations.
  
  
  CONCLUSIONS
  This study extends the mutation spectrum of COL4A3 and COL4A4 genes, and suggests a possible relationship between production of abnormal COL IV chains and dominant expression of a continuous spectrum of phenotypes, from ATS to BFH.
authors.affiliation: Genetica Medica, Università di Siena, Siena; Dip. Scienze Cliniche e Biologiche and Genetica, Biologia e Biochimica, Università di Torino, Torino, Italy. longo@unisi.it
authors.forename: Ilaria
authors.initials: I
authors.lastname: Longo
authors.forename: Paola
authors.initials: P
authors.lastname: Porcedda
authors.forename: Francesca
authors.initials: F
authors.lastname: Mari
authors.forename: Daniela
authors.initials: D
authors.lastname: Giachino
authors.forename: Ilaria
authors.initials: I
authors.lastname: Meloni
authors.forename: Carla
authors.initials: C
authors.lastname: Deplano
authors.forename: Alfredo
authors.initials: A
authors.lastname: Brusco
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bosio
authors.forename: Laura
authors.initials: L
authors.lastname: Massella
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Lavoratti
authors.forename: Dario
authors.initials: D
authors.lastname: Roccatello
authors.forename: Giovanni
authors.initials: G
authors.lastname: Frascá
authors.forename: Gianna
authors.initials: G
authors.lastname: Mazzucco
authors.forename: Andrea Onetti
authors.initials: AO
authors.lastname: Muda
authors.forename: Maura
authors.initials: M
authors.lastname: Conti
authors.forename: Federica
authors.initials: F
authors.lastname: Fasciolo
authors.forename: Christelle
authors.initials: C
authors.lastname: Arrondel
authors.forename: Laurence
authors.initials: L
authors.lastname: Heidet
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.forename: Mario
authors.initials: M
authors.lastname: De Marchi
mesh_terms: D000328:Adult; D000483:Alleles; D001324:Autoantigens / Q000235:genetics*; D001483:Base Sequence / Q000235:genetics; D024141:Collagen Type IV / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D006417:Hematuria / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009394:Nephritis, Hereditary / Q000235:genetics*; D010375:Pedigree
chemical_list: D001324:Autoantigens; C466620:COL4A4 protein, human; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain