title: X-linked Alport syndrome associated with a synonymous p.Gly292Gly mutation alters the splicing donor site of the type IV collagen alpha chain 5 gene.
abstract: BACKGROUND
  X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the type IV collagen alpha chain 5 gene (COL4A5). Although many COL4A5 mutations have previously been identified, pathogenic synonymous mutations have not yet been described.
  
  
  METHODS
  A family with XLAS underwent mutational analyses of COL4A5 by PCR and direct sequencing, as well as transcript analysis of potential splice site mutations. In silico analysis was also conducted to predict the disruption of splicing factor binding sites. Immunohistochemistry (IHC) of kidney biopsies was used to detect α2 and α5 chain expression.
  
  
  RESULTS
  We identified a hemizygous point mutation, c.876A>T, in exon 15 of COL4A5 in the proband and his brother, which is predicted to result in a synonymous amino acid change, p.(Gly292Gly). Transcript analysis showed that this mutation potentially altered splicing because it disrupted the splicing factor binding site. The kidney biopsy of the proband showed lamellation of the glomerular basement membrane (GBM), while IHC revealed negative α5(IV) staining in the GBM and Bowman's capsule, which is typical of XLAS.
  
  
  CONCLUSIONS
  This is the first report of a synonymous COL4A5 substitution being responsible for XLAS. Our findings suggest that transcript analysis should be conducted for the future correct assessment of silent mutations.
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 6500017, Japan.
authors.forename: Xue Jun
authors.initials: XJ
authors.lastname: Fu
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 6500017, Japan. nozu@med.kobe-u.ac.jp.
authors.forename: Kandai
authors.initials: K
authors.lastname: Nozu
authors.affiliation: Department of Nephrology, Saiseikai Kawaguchi General Hospital, Saitama, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Eguchi
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 6500017, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nozu
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 6500017, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Morisada
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 6500017, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Shono
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 6500017, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Taniguchi-Ikeda
authors.affiliation: Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shima
authors.affiliation: Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakanishi
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Igor
authors.initials: I
authors.lastname: Vorechovsky
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 6500017, Japan.
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Iijima
mesh_terms: D001706:Biopsy; D050476:Bowman Capsule / Q000737:chemistry; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D050533:Glomerular Basement Membrane / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009394:Nephritis, Hereditary / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D022821:RNA Splice Sites; D055815:Young Adult
chemical_list: C478159:COL4A5 protein, human; D024141:Collagen Type IV; D022821:RNA Splice Sites
keywords: COL4A5; Silent mutation; Splicing; Synonymous mutation