title: Somatic mosaicism for a mutation of the COL4A5 gene is a cause of mild phenotype male Alport syndrome.
abstract: BACKGROUND
  Alport syndrome is the most common form of hereditary nephritis and is mainly caused by mutations in the COL4A5 gene, which shows the X-linked form. It is well known that some male Alport syndrome cases show a relatively mild phenotype, but few molecular investigations have been conducted to clarify the mechanism of this phenotype. Methods and results. This report concerns an 8-year-old male sporadic Alport syndrome patient. While electron microscopy of the glomerular basement membrane showed typical findings for Alport syndrome, however, the immunohistochemical analysis of the glomerulus showed mosaic staining of the type IV collagen alpha 5 chain. The mutational analysis of the COL4A5 gene unexpectedly disclosed two peaks at the intron 43 splicing acceptor site (c. 3998-2 a/t) with direct sequencing. Restriction enzyme analysis demonstrated that the presence of somatic mosaicism was responsible for this mutation. mRNA extracted from the urinary sediments was analysed by RT-PCR and two PCR fragments were amplified, one consisting of a normal sequence and one with skipping of exon 44.
  
  
  CONCLUSIONS
  Our findings indicate that somatic mosaicism for COL4A5 is responsible for male X-linked Alport syndrome with an alpha 5 mosaic staining pattern. Several cases with somatic mosaicism have previously been reported, however, this is the first case where the presence of this mutation was proved with a comprehensive analysis of genomic DNA, mRNA and alpha 5 expression in the tissues. Somatic mosaicism may thus be one of the causes of the mild phenotype in Alport syndrome.
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Hyogo, Japan.
authors.forename: Rafal Przybyslaw
authors.initials: RP
authors.lastname: Krol
authors.forename: Kandai
authors.initials: K
authors.lastname: Nozu
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Iijima
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takeshima
authors.forename: Xue Jun
authors.initials: XJ
authors.lastname: Fu
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nozu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kaito
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kanda
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
authors.forename: Norishige
authors.initials: N
authors.lastname: Yoshikawa
mesh_terms: D001483:Base Sequence; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005091:Exons; D050533:Glomerular Basement Membrane / Q000378:metabolism / Q000473:pathology; D006417:Hematuria / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D009030:Mosaicism; D009154:Mutation; D009394:Nephritis, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011507:Proteinuria / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C478159:COL4A5 protein, human; D024141:Collagen Type IV; D017931:DNA Primers; D012333:RNA, Messenger; D004247:DNA