A Novel α-Galactosidase A Splicing Mutation Predisposes to Fabry Disease
Fabry disease (FD) is a rare X-linked α-galactosidase A (GLA) deficiency, resulting in progressive lysosomal accumulation of globotriaosylceramide (Gb3) in a variety of cell types. Here, we report a novel splicing mutation (c.801 + 1G > A) that results in alternative splicing in GLA of a FD p...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-02-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2019.00060/full |
| _version_ | 1818421029788188672 |
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| author | Ping Li Lijuan Zhang Na Zhao Qiuhong Xiong Yong-An Zhou Changxin Wu Han Xiao |
| author_facet | Ping Li Lijuan Zhang Na Zhao Qiuhong Xiong Yong-An Zhou Changxin Wu Han Xiao |
| author_sort | Ping Li |
| collection | DOAJ |
| description | Fabry disease (FD) is a rare X-linked α-galactosidase A (GLA) deficiency, resulting in progressive lysosomal accumulation of globotriaosylceramide (Gb3) in a variety of cell types. Here, we report a novel splicing mutation (c.801 + 1G > A) that results in alternative splicing in GLA of a FD patient with variable phenotypic presentations of renal involvement. Sequencing of the RT-PCR products from the patient’s blood sample reveals a 36-nucleotide (nt) insertion exists at the junction between exons 5 and 6 of the GLA cDNA. Splicing assay indicates that the mutated minigene produces an alternatively spliced transcript which causes a frameshift resulting in an early termination of protein expression. Immunofluorescence shows puncta in cytoplasm for mutated GLA whereas uniform staining small dots evenly distributed inside cytoplasm for wild type GLA in transfected HeLa cells. The increased senescence and decreased GLA enzyme activity suggest that the abnormalities might be due to the altered localization which further might result from the lack of the C-terminal end of GLA. Our study reveals the pathogenesis of splicing mutation c.801 + 1G > A to FD and provides scientific foundation for accurate diagnosis and precise medical intervention for FD. |
| first_indexed | 2024-12-14T13:03:52Z |
| format | Article |
| id | doaj.art-e3c031b5a8a54884b2a15090f787c1fd |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-14T13:03:52Z |
| publishDate | 2019-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-e3c031b5a8a54884b2a15090f787c1fd2022-12-21T23:00:21ZengFrontiers Media S.A.Frontiers in Genetics1664-80212019-02-011010.3389/fgene.2019.00060416439A Novel α-Galactosidase A Splicing Mutation Predisposes to Fabry DiseasePing Li0Lijuan Zhang1Na Zhao2Qiuhong Xiong3Yong-An Zhou4Changxin Wu5Han Xiao6Institutes of Biomedical Sciences, Shanxi University, Taiyuan, ChinaInstitutes of Biomedical Sciences, Shanxi University, Taiyuan, ChinaInstitutes of Biomedical Sciences, Shanxi University, Taiyuan, ChinaInstitutes of Biomedical Sciences, Shanxi University, Taiyuan, ChinaBluttransfusion, The Second Hospital, Shanxi Medical University, Taiyuan, ChinaInstitutes of Biomedical Sciences, Shanxi University, Taiyuan, ChinaInstitutes of Biomedical Sciences, Shanxi University, Taiyuan, ChinaFabry disease (FD) is a rare X-linked α-galactosidase A (GLA) deficiency, resulting in progressive lysosomal accumulation of globotriaosylceramide (Gb3) in a variety of cell types. Here, we report a novel splicing mutation (c.801 + 1G > A) that results in alternative splicing in GLA of a FD patient with variable phenotypic presentations of renal involvement. Sequencing of the RT-PCR products from the patient’s blood sample reveals a 36-nucleotide (nt) insertion exists at the junction between exons 5 and 6 of the GLA cDNA. Splicing assay indicates that the mutated minigene produces an alternatively spliced transcript which causes a frameshift resulting in an early termination of protein expression. Immunofluorescence shows puncta in cytoplasm for mutated GLA whereas uniform staining small dots evenly distributed inside cytoplasm for wild type GLA in transfected HeLa cells. The increased senescence and decreased GLA enzyme activity suggest that the abnormalities might be due to the altered localization which further might result from the lack of the C-terminal end of GLA. Our study reveals the pathogenesis of splicing mutation c.801 + 1G > A to FD and provides scientific foundation for accurate diagnosis and precise medical intervention for FD.https://www.frontiersin.org/article/10.3389/fgene.2019.00060/fullFabry diseaseGLAsplicing mutationc.801 + 1G > Anovel mutation |
| spellingShingle | Ping Li Lijuan Zhang Na Zhao Qiuhong Xiong Yong-An Zhou Changxin Wu Han Xiao A Novel α-Galactosidase A Splicing Mutation Predisposes to Fabry Disease Frontiers in Genetics Fabry disease GLA splicing mutation c.801 + 1G > A novel mutation |
| title | A Novel α-Galactosidase A Splicing Mutation Predisposes to Fabry Disease |
| title_full | A Novel α-Galactosidase A Splicing Mutation Predisposes to Fabry Disease |
| title_fullStr | A Novel α-Galactosidase A Splicing Mutation Predisposes to Fabry Disease |
| title_full_unstemmed | A Novel α-Galactosidase A Splicing Mutation Predisposes to Fabry Disease |
| title_short | A Novel α-Galactosidase A Splicing Mutation Predisposes to Fabry Disease |
| title_sort | novel α galactosidase a splicing mutation predisposes to fabry disease |
| topic | Fabry disease GLA splicing mutation c.801 + 1G > A novel mutation |
| url | https://www.frontiersin.org/article/10.3389/fgene.2019.00060/full |
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