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All reported non-canonical splice site variants in GLA cause aberrant splicing

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by insufficient α-galactosidase A (GLA) activity resulting from variants in the GLA gene, which leads to glycosphingolipid accumulation and life-threatening, multi-organ complications. Approximately 50 variants have been repo...

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Autores principales: Okada, Eri, Horinouchi, Tomoko, Yamamura, Tomohiko, Aoto, Yuya, Suzuki, Ryota, Ichikawa, Yuta, Tanaka, Yu, Masuda, Chika, Kitakado, Hideaki, Kondo, Atsushi, Sakakibara, Nana, Ishiko, Shinya, Nagano, China, Ishimori, Shingo, Usui, Joichi, Yamagata, Kunihiro, Matsuo, Masafumi, Nozu, Kandai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Nature Singapore 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10432374/
https://www.ncbi.nlm.nih.gov/pubmed/37254000
http://dx.doi.org/10.1007/s10157-023-02361-x
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author Okada, Eri
Horinouchi, Tomoko
Yamamura, Tomohiko
Aoto, Yuya
Suzuki, Ryota
Ichikawa, Yuta
Tanaka, Yu
Masuda, Chika
Kitakado, Hideaki
Kondo, Atsushi
Sakakibara, Nana
Ishiko, Shinya
Nagano, China
Ishimori, Shingo
Usui, Joichi
Yamagata, Kunihiro
Matsuo, Masafumi
Nozu, Kandai
author_facet Okada, Eri
Horinouchi, Tomoko
Yamamura, Tomohiko
Aoto, Yuya
Suzuki, Ryota
Ichikawa, Yuta
Tanaka, Yu
Masuda, Chika
Kitakado, Hideaki
Kondo, Atsushi
Sakakibara, Nana
Ishiko, Shinya
Nagano, China
Ishimori, Shingo
Usui, Joichi
Yamagata, Kunihiro
Matsuo, Masafumi
Nozu, Kandai
author_sort Okada, Eri
collection PubMed
description BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by insufficient α-galactosidase A (GLA) activity resulting from variants in the GLA gene, which leads to glycosphingolipid accumulation and life-threatening, multi-organ complications. Approximately 50 variants have been reported that cause splicing abnormalities in GLA. Most were found within canonical splice sites, which are highly conserved GT and AG splice acceptor and donor dinucleotides, whereas one-third were located outside canonical splice sites, making it difficult to interpret their pathogenicity. In this study, we aimed to investigate the genetic pathogenicity of variants located in non-canonical splice sites within the GLA gene. METHODS: 13 variants, including four deep intronic variants, were selected from the Human Gene Variant Database Professional. We performed an in vitro splicing assay to identify splicing abnormalities in the variants. RESULTS: All candidate non-canonical splice site variants in GLA caused aberrant splicing. Additionally, all but one variant was protein-truncating. The four deep intronic variants generated abnormal transcripts, including a cryptic exon, as well as normal transcripts, with the proportion of each differing in a cell-specific manner. CONCLUSIONS: Validation of splicing effects using an in vitro splicing assay is useful for confirming pathogenicity and determining associations with clinical phenotypes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10157-023-02361-x.
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spelling pubmed-104323742023-08-18 All reported non-canonical splice site variants in GLA cause aberrant splicing Okada, Eri Horinouchi, Tomoko Yamamura, Tomohiko Aoto, Yuya Suzuki, Ryota Ichikawa, Yuta Tanaka, Yu Masuda, Chika Kitakado, Hideaki Kondo, Atsushi Sakakibara, Nana Ishiko, Shinya Nagano, China Ishimori, Shingo Usui, Joichi Yamagata, Kunihiro Matsuo, Masafumi Nozu, Kandai Clin Exp Nephrol Original Article BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by insufficient α-galactosidase A (GLA) activity resulting from variants in the GLA gene, which leads to glycosphingolipid accumulation and life-threatening, multi-organ complications. Approximately 50 variants have been reported that cause splicing abnormalities in GLA. Most were found within canonical splice sites, which are highly conserved GT and AG splice acceptor and donor dinucleotides, whereas one-third were located outside canonical splice sites, making it difficult to interpret their pathogenicity. In this study, we aimed to investigate the genetic pathogenicity of variants located in non-canonical splice sites within the GLA gene. METHODS: 13 variants, including four deep intronic variants, were selected from the Human Gene Variant Database Professional. We performed an in vitro splicing assay to identify splicing abnormalities in the variants. RESULTS: All candidate non-canonical splice site variants in GLA caused aberrant splicing. Additionally, all but one variant was protein-truncating. The four deep intronic variants generated abnormal transcripts, including a cryptic exon, as well as normal transcripts, with the proportion of each differing in a cell-specific manner. CONCLUSIONS: Validation of splicing effects using an in vitro splicing assay is useful for confirming pathogenicity and determining associations with clinical phenotypes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10157-023-02361-x. Springer Nature Singapore 2023-05-31 2023 /pmc/articles/PMC10432374/ /pubmed/37254000 http://dx.doi.org/10.1007/s10157-023-02361-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Okada, Eri
Horinouchi, Tomoko
Yamamura, Tomohiko
Aoto, Yuya
Suzuki, Ryota
Ichikawa, Yuta
Tanaka, Yu
Masuda, Chika
Kitakado, Hideaki
Kondo, Atsushi
Sakakibara, Nana
Ishiko, Shinya
Nagano, China
Ishimori, Shingo
Usui, Joichi
Yamagata, Kunihiro
Matsuo, Masafumi
Nozu, Kandai
All reported non-canonical splice site variants in GLA cause aberrant splicing
title All reported non-canonical splice site variants in GLA cause aberrant splicing
title_full All reported non-canonical splice site variants in GLA cause aberrant splicing
title_fullStr All reported non-canonical splice site variants in GLA cause aberrant splicing
title_full_unstemmed All reported non-canonical splice site variants in GLA cause aberrant splicing
title_short All reported non-canonical splice site variants in GLA cause aberrant splicing
title_sort all reported non-canonical splice site variants in gla cause aberrant splicing
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10432374/
https://www.ncbi.nlm.nih.gov/pubmed/37254000
http://dx.doi.org/10.1007/s10157-023-02361-x
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