Document Detail

X-Linked Alport Syndrome Caused by Splicing Mutations in COL4A5.
MedLine Citation:
PMID:  25183659     Owner:  NLM     Status:  In-Data-Review    
BACKGROUND AND OBJECTIVES: X-linked Alport syndrome is caused by mutations in the COL4A5 gene. Although many COL4A5 mutations have been detected, the mutation detection rate has been unsatisfactory. Some men with X-linked Alport syndrome show a relatively mild phenotype, but molecular basis investigations have rarely been conducted to clarify the underlying mechanism.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 152 patients with X-linked Alport syndrome who were suspected of having Alport syndrome through clinical and pathologic investigations and referred to the hospital for mutational analysis between January of 2006 and January of 2013 were genetically diagnosed. Among those patients, 22 patients had suspected splice site mutations. Transcripts are routinely examined when suspected splice site mutations for abnormal transcripts are detected; 11 of them showed expected exon skipping, but others showed aberrant splicing patterns. The mutation detection strategy had two steps: (1) genomic DNA analysis using PCR and direct sequencing and (2) mRNA analysis using RT-PCR to detect RNA processing abnormalities.
RESULTS: Six splicing consensus site mutations resulting in aberrant splicing patterns, one exonic mutation leading to exon skipping, and four deep intronic mutations producing cryptic splice site activation were identified. Interestingly, one case produced a cryptic splice site with a single nucleotide substitution in the deep intron that led to intronic exonization containing a stop codon; however, the patient showed a clearly milder phenotype for X-linked Alport syndrome in men with a truncating mutation. mRNA extracted from the kidney showed both normal and abnormal transcripts, with the normal transcript resulting in the milder phenotype. This novel mechanism leads to mild clinical characteristics.
CONCLUSIONS: This report highlights the importance of analyzing transcripts to enhance the mutation detection rate and provides insight into genotype-phenotype correlations. This approach can clarify the cause of atypically mild phenotypes in X-linked Alport syndrome.
Kandai Nozu; Igor Vorechovsky; Hiroshi Kaito; Xue Jun Fu; Koichi Nakanishi; Yuya Hashimura; Fusako Hashimoto; Koichi Kamei; Shuichi Ito; Yoshitsugu Kaku; Toshiyuki Imasawa; Katsumi Ushijima; Junya Shimizu; Yoshio Makita; Takao Konomoto; Norishige Yoshikawa; Kazumoto Iijima
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Publication Detail:
Type:  Journal Article     Date:  2014-09-02
Journal Detail:
Title:  Clinical journal of the American Society of Nephrology : CJASN     Volume:  9     ISSN:  1555-905X     ISO Abbreviation:  Clin J Am Soc Nephrol     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-11-08     Completed Date:  -     Revised Date:  2014-12-04    
Medline Journal Info:
Nlm Unique ID:  101271570     Medline TA:  Clin J Am Soc Nephrol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1958-64     Citation Subset:  IM    
Copyright Information:
Copyright © 2014 by the American Society of Nephrology.
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