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Fabry disease: GLA deletion alters a canonical splice site in a family with neuropsychiatric manifestations
Fabry disease (FD) is a rare X-linked glycosphingolipidosis caused by mutations in GLA, a gene responsible for encoding α-galactosidase A, an enzyme required for degradation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in all cells of the body. FD patients present a broad spectrum of cl...
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| Published in: | Metabolic brain disease 2021-02, Vol.36 (2), p.265-272 |
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| container_title | Metabolic brain disease |
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| creator | Varela, Patrícia Carvalho, Gerson Martin, Renan Paulo Pesquero, João Bosco |
| description | Fabry disease (FD) is a rare X-linked glycosphingolipidosis caused by mutations in
GLA,
a gene responsible for encoding α-galactosidase A, an enzyme required for degradation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in all cells of the body. FD patients present a broad spectrum of clinical phenotype and many symptoms are shared with other diseases, making diagnosis challenging. Here we describe a novel
GLA
variant located in the 5′ splice site of the intron 3, in four members of a family with neuropsychiatric symptoms. Analysis of the RNA showed the variant promotes alteration of the wild type donor site, affecting splicing and producing two aberrant transcripts. The functional characterization showed absence of enzymatic activity in cells expressing both transcripts, confirming their pathogenicity. The family presents mild signs of FD, as angiokeratoma, cornea verticillata, acroparesthesia, tinnitus, vertigo, as well as accumulation of plasma lyso-Gb3 and urinary Gb3. Interestingly, the man and two women present psychiatric symptoms, as depression or schizophrenia. Although psychiatric illnesses, especially depression, are frequently reported in patients with FD and studies have shown that the hippocampus is an affected brain structure in these patients, it is not clear whether the Gb3 accumulation in the brain is responsible for these symptoms or they are secondary. Therefore, new studies are needed to understand whether the accumulation of Gb3 could produce neuronal alterations leading to psychiatric symptoms. |
| doi_str_mv | 10.1007/s11011-020-00640-0 |
| format | article |
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GLA,
a gene responsible for encoding α-galactosidase A, an enzyme required for degradation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in all cells of the body. FD patients present a broad spectrum of clinical phenotype and many symptoms are shared with other diseases, making diagnosis challenging. Here we describe a novel
GLA
variant located in the 5′ splice site of the intron 3, in four members of a family with neuropsychiatric symptoms. Analysis of the RNA showed the variant promotes alteration of the wild type donor site, affecting splicing and producing two aberrant transcripts. The functional characterization showed absence of enzymatic activity in cells expressing both transcripts, confirming their pathogenicity. The family presents mild signs of FD, as angiokeratoma, cornea verticillata, acroparesthesia, tinnitus, vertigo, as well as accumulation of plasma lyso-Gb3 and urinary Gb3. Interestingly, the man and two women present psychiatric symptoms, as depression or schizophrenia. Although psychiatric illnesses, especially depression, are frequently reported in patients with FD and studies have shown that the hippocampus is an affected brain structure in these patients, it is not clear whether the Gb3 accumulation in the brain is responsible for these symptoms or they are secondary. Therefore, new studies are needed to understand whether the accumulation of Gb3 could produce neuronal alterations leading to psychiatric symptoms.</description><identifier>ISSN: 0885-7490</identifier><identifier>EISSN: 1573-7365</identifier><identifier>DOI: 10.1007/s11011-020-00640-0</identifier><identifier>PMID: 33156427</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Accumulation ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Brain ; Cornea ; Enzymatic activity ; Fabry's disease ; Families & family life ; Galactosidase ; Globotriaosylceramide ; Glycosphingolipids ; Mental depression ; Mental disorders ; Metabolic Diseases ; Mutation ; Neurology ; Neurosciences ; Oncology ; Original Article ; Pathogenicity ; Pathogens ; Phenotypes ; Ribonucleic acid ; RNA ; Schizophrenia ; Signs and symptoms ; Tinnitus ; Vertigo</subject><ispartof>Metabolic brain disease, 2021-02, Vol.36 (2), p.265-272</ispartof><rights>Springer Science+Business Media, LLC, part of Springer Nature 2020</rights><rights>Springer Science+Business Media, LLC, part of Springer Nature 2020.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-e9df6d31edf66c7bfb22256dc4482ebffd5f30d1b86b9b980c8d2e0812e4af1e3</citedby><cites>FETCH-LOGICAL-c375t-e9df6d31edf66c7bfb22256dc4482ebffd5f30d1b86b9b980c8d2e0812e4af1e3</cites><orcidid>0000-0002-4507-632X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33156427$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Varela, Patrícia</creatorcontrib><creatorcontrib>Carvalho, Gerson</creatorcontrib><creatorcontrib>Martin, Renan Paulo</creatorcontrib><creatorcontrib>Pesquero, João Bosco</creatorcontrib><title>Fabry disease: GLA deletion alters a canonical splice site in a family with neuropsychiatric manifestations</title><title>Metabolic brain disease</title><addtitle>Metab Brain Dis</addtitle><addtitle>Metab Brain Dis</addtitle><description>Fabry disease (FD) is a rare X-linked glycosphingolipidosis caused by mutations in
GLA,
a gene responsible for encoding α-galactosidase A, an enzyme required for degradation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in all cells of the body. FD patients present a broad spectrum of clinical phenotype and many symptoms are shared with other diseases, making diagnosis challenging. Here we describe a novel
GLA
variant located in the 5′ splice site of the intron 3, in four members of a family with neuropsychiatric symptoms. Analysis of the RNA showed the variant promotes alteration of the wild type donor site, affecting splicing and producing two aberrant transcripts. The functional characterization showed absence of enzymatic activity in cells expressing both transcripts, confirming their pathogenicity. The family presents mild signs of FD, as angiokeratoma, cornea verticillata, acroparesthesia, tinnitus, vertigo, as well as accumulation of plasma lyso-Gb3 and urinary Gb3. Interestingly, the man and two women present psychiatric symptoms, as depression or schizophrenia. Although psychiatric illnesses, especially depression, are frequently reported in patients with FD and studies have shown that the hippocampus is an affected brain structure in these patients, it is not clear whether the Gb3 accumulation in the brain is responsible for these symptoms or they are secondary. Therefore, new studies are needed to understand whether the accumulation of Gb3 could produce neuronal alterations leading to psychiatric symptoms.</description><subject>Accumulation</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain</subject><subject>Cornea</subject><subject>Enzymatic activity</subject><subject>Fabry's disease</subject><subject>Families & family life</subject><subject>Galactosidase</subject><subject>Globotriaosylceramide</subject><subject>Glycosphingolipids</subject><subject>Mental depression</subject><subject>Mental disorders</subject><subject>Metabolic Diseases</subject><subject>Mutation</subject><subject>Neurology</subject><subject>Neurosciences</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Pathogenicity</subject><subject>Pathogens</subject><subject>Phenotypes</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Schizophrenia</subject><subject>Signs and symptoms</subject><subject>Tinnitus</subject><subject>Vertigo</subject><issn>0885-7490</issn><issn>1573-7365</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kU9vFDEMxSMEokvhC3BAkbhwGXCSSSbDrapoQVqJC5yjTOLQlPmzxDOq9tuTsgUkDlz8Dv752fJj7KWAtwKge0dCgBANSGgATFvrI7YTulNNp4x-zHZgrW66tocz9ozoFgCUFv1TdqaU0KaV3Y59v_JDOfKYCT3he369v-ARR1zzMnM_rliIex78vMw5-JHTYcwBOeUVea4ET37K45Hf5fWGz7iV5UDHcJP9WnLgk59zQlr9vR09Z0-SHwlfPOg5-3r14cvlx2b_-frT5cW-CarTa4N9TCYqgVVM6IY0SCm1iaFtrcQhpaiTgigGa4Z-6C0EGyWCFRJbnwSqc_bm5Hsoy4-trndTpoDj6GdcNnKy1RaUaZWq6Ot_0NtlK3O9rlKdNUZbaSslT1QoC1HB5A4lT74cnQB3H4U7ReFqFO5XFA7q0KsH622YMP4Z-f37CqgTQLU1f8Pyd_d_bH8Cr52VFQ</recordid><startdate>20210201</startdate><enddate>20210201</enddate><creator>Varela, Patrícia</creator><creator>Carvalho, Gerson</creator><creator>Martin, Renan Paulo</creator><creator>Pesquero, João Bosco</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TK</scope><scope>7U7</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4507-632X</orcidid></search><sort><creationdate>20210201</creationdate><title>Fabry disease: GLA deletion alters a canonical splice site in a family with neuropsychiatric manifestations</title><author>Varela, Patrícia ; Carvalho, Gerson ; Martin, Renan Paulo ; Pesquero, João Bosco</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-e9df6d31edf66c7bfb22256dc4482ebffd5f30d1b86b9b980c8d2e0812e4af1e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Accumulation</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain</topic><topic>Cornea</topic><topic>Enzymatic activity</topic><topic>Fabry's disease</topic><topic>Families & family life</topic><topic>Galactosidase</topic><topic>Globotriaosylceramide</topic><topic>Glycosphingolipids</topic><topic>Mental depression</topic><topic>Mental disorders</topic><topic>Metabolic Diseases</topic><topic>Mutation</topic><topic>Neurology</topic><topic>Neurosciences</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Pathogenicity</topic><topic>Pathogens</topic><topic>Phenotypes</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Schizophrenia</topic><topic>Signs and symptoms</topic><topic>Tinnitus</topic><topic>Vertigo</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Varela, Patrícia</creatorcontrib><creatorcontrib>Carvalho, Gerson</creatorcontrib><creatorcontrib>Martin, Renan Paulo</creatorcontrib><creatorcontrib>Pesquero, João Bosco</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Psychology Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Metabolic brain disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Varela, Patrícia</au><au>Carvalho, Gerson</au><au>Martin, Renan Paulo</au><au>Pesquero, João Bosco</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fabry disease: GLA deletion alters a canonical splice site in a family with neuropsychiatric manifestations</atitle><jtitle>Metabolic brain disease</jtitle><stitle>Metab Brain Dis</stitle><addtitle>Metab Brain Dis</addtitle><date>2021-02-01</date><risdate>2021</risdate><volume>36</volume><issue>2</issue><spage>265</spage><epage>272</epage><pages>265-272</pages><issn>0885-7490</issn><eissn>1573-7365</eissn><notes>ObjectType-Case Study-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-4</notes><notes>content type line 23</notes><notes>ObjectType-Report-1</notes><notes>ObjectType-Article-3</notes><abstract>Fabry disease (FD) is a rare X-linked glycosphingolipidosis caused by mutations in
GLA,
a gene responsible for encoding α-galactosidase A, an enzyme required for degradation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in all cells of the body. FD patients present a broad spectrum of clinical phenotype and many symptoms are shared with other diseases, making diagnosis challenging. Here we describe a novel
GLA
variant located in the 5′ splice site of the intron 3, in four members of a family with neuropsychiatric symptoms. Analysis of the RNA showed the variant promotes alteration of the wild type donor site, affecting splicing and producing two aberrant transcripts. The functional characterization showed absence of enzymatic activity in cells expressing both transcripts, confirming their pathogenicity. The family presents mild signs of FD, as angiokeratoma, cornea verticillata, acroparesthesia, tinnitus, vertigo, as well as accumulation of plasma lyso-Gb3 and urinary Gb3. Interestingly, the man and two women present psychiatric symptoms, as depression or schizophrenia. Although psychiatric illnesses, especially depression, are frequently reported in patients with FD and studies have shown that the hippocampus is an affected brain structure in these patients, it is not clear whether the Gb3 accumulation in the brain is responsible for these symptoms or they are secondary. Therefore, new studies are needed to understand whether the accumulation of Gb3 could produce neuronal alterations leading to psychiatric symptoms.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>33156427</pmid><doi>10.1007/s11011-020-00640-0</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-4507-632X</orcidid></addata></record> |
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| ispartof | Metabolic brain disease, 2021-02, Vol.36 (2), p.265-272 |
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| source | Springer Nature:Jisc Collections:Springer Nature Read and Publish 2023-2025: Springer Reading List |
| subjects | Accumulation Biochemistry Biomedical and Life Sciences Biomedicine Brain Cornea Enzymatic activity Fabry's disease Families & family life Galactosidase Globotriaosylceramide Glycosphingolipids Mental depression Mental disorders Metabolic Diseases Mutation Neurology Neurosciences Oncology Original Article Pathogenicity Pathogens Phenotypes Ribonucleic acid RNA Schizophrenia Signs and symptoms Tinnitus Vertigo |
| title | Fabry disease: GLA deletion alters a canonical splice site in a family with neuropsychiatric manifestations |
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