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Title :Pathogenic evaluation of synonymous COL4A5 variants in X-linked Alport syndrome using a minigene assay
Authors :Horinouchi, Tomoko
Yamamura, Tomohiko
Minamikawa, Shogo
Nagano, China
Sakakibara, Nana
Nakanishi, Koichi
Shima, Yuko
Morisada, Naoya
Ishiko, Shinya
Aoto, Yuya
Nagase, Hiroaki
Takeda, Hiroki
Rossanti, Rini
Ishimori, Shingo
Kaito, Hiroshi
Matsuo, Masafumi
Iijima, Kazumoto
Nozu, Kandai
Issue Date :2020
Abstract :Background: X-linked Alport syndrome (XLAS) is a progressive, hereditary glomerular nephritis of variable severity caused by pathogenic COL4A5 variants. Currently, genetic testing is widely used for diagnosing XLAS; however, determining the pathogenicity of variants detected by such analyses can be difficult. Intronic variants or synonymous variants may cause inherited diseases by inducing aberrant splicing. Transcript analysis is necessary to confirm the pathogenicity of such variants, but it is sometimes difficult to extract mRNA directly from patient specimens. Methods: In this study, we conducted in vitro splicing analysis using a hybrid minigene assay and specimens from three XLAS patients with synonymous variants causing aberrant splicing, including previously reported pathogenic mutations in the same codon. The variants were c.876 A>T (p.Gly292=), c.2358 A>G (p.Pro786=), and c.3906 A>G (p.Gln1302=). Results: The results from our hybrid minigene assay were sufficient to predict splicing abnormalities; c.876 A>T cause 17-bp del and 35-bp del, c.2358 A>G cause exon 29 skipping, c.3906 A>G cause exon 42 skipping, which are very likely to cause pathogenicity. Further, patients carrying c.2358 A>G exhibited a mild phenotype that may have been associated with the presence of both normal and abnormally spliced transcripts. Conclusion: The minigene system was shown to be a sensitive assay and a useful tool for investigating the pathogenicity of synonymous variants.
URL :https://doi.org/10.1002/mgg3.1342
Type Local :雑誌掲載論文
ISSN :2324-9269
Publisher :Wiley Open Access
URI :http://hdl.handle.net/20.500.12000/46926
Citation :Molecular Genetics and Genomic Medicine Vol.8 no.8
Appears in Collections:Peer-reviewed Journal Articles (Faculty of Medicine)

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