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

Xue Jun Fu, Kandai Nozu, Aya Eguchi, Yoshimi Nozu, Naoya Morisada, Akemi Shono, Mariko Ikeda, Yuko Shima, Koichi Nakanishi, Igor Vorechovsky, Kazumoto Iijima

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)699-702
Number of pages4
JournalClinical and Experimental Nephrology
Volume20
Issue number5
DOIs
Publication statusPublished - 01-10-2016

Fingerprint

Hereditary Nephritis
Collagen Type IV
Glomerular Basement Membrane
Mutation
Genes
Immunohistochemistry
Binding Sites
Bowman Capsule
Kidney
Biopsy
Point Mutation
Computer Simulation
Exons
Staining and Labeling
Amino Acids
Polymerase Chain Reaction
RNA Splicing Factors
Silent Mutation

All Science Journal Classification (ASJC) codes

  • Physiology
  • Nephrology
  • Physiology (medical)

Cite this

Fu, Xue Jun ; Nozu, Kandai ; Eguchi, Aya ; Nozu, Yoshimi ; Morisada, Naoya ; Shono, Akemi ; Ikeda, Mariko ; Shima, Yuko ; Nakanishi, Koichi ; Vorechovsky, Igor ; Iijima, Kazumoto. / 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. In: Clinical and Experimental Nephrology. 2016 ; Vol. 20, No. 5. pp. 699-702.
@article{cd619acd25c94780ac29cf12466b009c,
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.",
author = "Fu, {Xue Jun} and Kandai Nozu and Aya Eguchi and Yoshimi Nozu and Naoya Morisada and Akemi Shono and Mariko Ikeda and Yuko Shima and Koichi Nakanishi and Igor Vorechovsky and Kazumoto Iijima",
year = "2016",
month = "10",
day = "1",
doi = "10.1007/s10157-015-1197-9",
language = "English",
volume = "20",
pages = "699--702",
journal = "Clinical and Experimental Nephrology",
issn = "1342-1751",
publisher = "Springer Japan",
number = "5",

}

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. / Fu, Xue Jun; Nozu, Kandai; Eguchi, Aya; Nozu, Yoshimi; Morisada, Naoya; Shono, Akemi; Ikeda, Mariko; Shima, Yuko; Nakanishi, Koichi; Vorechovsky, Igor; Iijima, Kazumoto.

In: Clinical and Experimental Nephrology, Vol. 20, No. 5, 01.10.2016, p. 699-702.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Fu, Xue Jun

AU - Nozu, Kandai

AU - Eguchi, Aya

AU - Nozu, Yoshimi

AU - Morisada, Naoya

AU - Shono, Akemi

AU - Ikeda, Mariko

AU - Shima, Yuko

AU - Nakanishi, Koichi

AU - Vorechovsky, Igor

AU - Iijima, Kazumoto

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84947446839&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84947446839&partnerID=8YFLogxK

U2 - 10.1007/s10157-015-1197-9

DO - 10.1007/s10157-015-1197-9

M3 - Article

C2 - 26581810

AN - SCOPUS:84947446839

VL - 20

SP - 699

EP - 702

JO - Clinical and Experimental Nephrology

JF - Clinical and Experimental Nephrology

SN - 1342-1751

IS - 5

ER -