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.

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  • Additional Information
    • Source:
      Publisher: Springer Country of Publication: Japan NLM ID: 9709923 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1437-7799 (Electronic) Linking ISSN: 13421751 NLM ISO Abbreviation: Clin Exp Nephrol Subsets: MEDLINE
    • Publication Information:
      Publication: 2008- : Tokyo : Springer
      Original Publication: Tokyo : Published for the Japanese Society of Nephrology by Churchill Livingstone, c1997-
    • Subject Terms:
      Point Mutation* ; RNA Splice Sites*; Collagen Type IV/*genetics ; Nephritis, Hereditary/*genetics; Biopsy ; Bowman Capsule/chemistry ; Collagen Type IV/metabolism ; DNA Mutational Analysis ; Disease Progression ; Exons ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Glomerular Basement Membrane/chemistry ; Humans ; Immunohistochemistry ; Kidney Failure, Chronic/diagnosis ; Kidney Failure, Chronic/genetics ; Kidney Failure, Chronic/metabolism ; Male ; Middle Aged ; Nephritis, Hereditary/diagnosis ; Nephritis, Hereditary/metabolism ; Pedigree ; Phenotype ; Young Adult
    • 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.
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    • Contributed Indexing:
      Keywords: COL4A5; Silent mutation; Splicing; Synonymous mutation
    • Accession Number:
      0 (COL4A5 protein, human)
      0 (Collagen Type IV)
      0 (RNA Splice Sites)
    • Publication Date:
      Date Created: 20151120 Date Completed: 20170411 Latest Revision: 20181113
    • Publication Date:
      20221213
    • Accession Number:
      10.1007/s10157-015-1197-9
    • Accession Number:
      26581810