Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure
Background Fabry disease (FD) is an X‐linked lysosomal storage and multi‐system disorder due to mutations in the α‐galactosidase A (α‐GalA) gene. We investigated the impact of individual amino acid exchanges in the α‐GalA 3D‐structure on the clinical phenotype of FD patients. Patients and methods We...
Gespeichert in:
| Veröffentlicht in: | Journal of internal medicine 2020-11, Vol.288 (5), p.593-604 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 604 |
|---|---|
| container_issue | 5 |
| container_start_page | 593 |
| container_title | Journal of internal medicine |
| container_volume | 288 |
| creator | Rickert, V. Wagenhäuser, L. Nordbeck, P. Wanner, C. Sommer, C. Rost, S. Üçeyler, N. |
| description | Background
Fabry disease (FD) is an X‐linked lysosomal storage and multi‐system disorder due to mutations in the α‐galactosidase A (α‐GalA) gene. We investigated the impact of individual amino acid exchanges in the α‐GalA 3D‐structure on the clinical phenotype of FD patients.
Patients and methods
We enrolled 80 adult FD patients with α‐GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α‐GalA 3D‐structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD‐specific treatment.
Results
Patients with active site or buried mutations showed a severe phenotype with multi‐organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α‐GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P |
| doi_str_mv | 10.1111/joim.13125 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmed_primary_32583479</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2417405964</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3935-eefa0489efba46b3a3710b4be61661159fa649219b5d5808465993281ce460073</originalsourceid><addsrcrecordid>eNqNkU9u1DAYxS1ERacDGw6ALLFBrVL8PzG7aqC0qKgLYB05ni_IgxMPtiM0O47AVbgIh-hJcJuhCxYIL2zr6fc9PX0PoaeUnNJyXm6CG04pp0w-QAvKlaxYrdVDtCBaiko1jByio5Q2hFBOFHmEDjmTDRe1XiD_IUeTXe9sucOIQ4_PTRd3eJjynZKwG7H1biyEx9tobHYWXmFTxJAgYh_CF2wy_vXz5vuPz8YXICS3NgnwWVH4a5xynGyeIjxGB73xCZ7s3yX6dP7m4-qiurp-e7k6u6os11xWAL0hotHQd0aojhteU9KJDhRVilKpe6OEZlR3ci0b0gglteasoRaEIqTmS_Ri9t3G8HWClNvBJQvemxHClFomaC2I1EoU9Plf6CZMcSzpCiUZ43UxLtTxTNkYUorQt9voBhN3LSXtbQftbQftXQcFfra3nLoB1vfon6UX4GQGvkEX-mQdjBbuMUKIFEyWRZRfaWyJmv-nV25ubRWmMZdRuh91Hnb_yNy-u758P6f_DXlos3I</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2452237328</pqid></control><display><type>article</type><title>Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Access via Wiley Online Library</source><source>Web of Science - Science Citation Index Expanded - 2020<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /></source><source>Wiley Online Library (Open Access Collection)</source><creator>Rickert, V. ; Wagenhäuser, L. ; Nordbeck, P. ; Wanner, C. ; Sommer, C. ; Rost, S. ; Üçeyler, N.</creator><creatorcontrib>Rickert, V. ; Wagenhäuser, L. ; Nordbeck, P. ; Wanner, C. ; Sommer, C. ; Rost, S. ; Üçeyler, N.</creatorcontrib><description>Background
Fabry disease (FD) is an X‐linked lysosomal storage and multi‐system disorder due to mutations in the α‐galactosidase A (α‐GalA) gene. We investigated the impact of individual amino acid exchanges in the α‐GalA 3D‐structure on the clinical phenotype of FD patients.
Patients and methods
We enrolled 80 adult FD patients with α‐GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α‐GalA 3D‐structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD‐specific treatment.
Results
Patients with active site or buried mutations showed a severe phenotype with multi‐organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α‐GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso‐Gb3 levels were higher (P < 0.01 in men; <0.05 in women).
Conclusions
The type of amino acid exchange location in the α‐GalA 3D‐structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.</description><identifier>ISSN: 0954-6820</identifier><identifier>EISSN: 1365-2796</identifier><identifier>DOI: 10.1111/joim.13125</identifier><identifier>PMID: 32583479</identifier><language>eng</language><publisher>HOBOKEN: Wiley</publisher><subject>alpha-Galactosidase - genetics ; Amino acids ; Buried structures ; Exchanging ; Fabry disease ; Fabry Disease - complications ; Fabry Disease - diagnosis ; Fabry Disease - enzymology ; Fabry Disease - genetics ; Fabry genotype ; Fabry phenotype ; Fabry's disease ; Galactosidase ; General & Internal Medicine ; Genotype & phenotype ; Humans ; Life Sciences & Biomedicine ; lyso‐Gb3 ; Medicine, General & Internal ; Missense mutation ; Molecular Conformation ; Mutation ; Mutation, Missense ; Parameters ; Patients ; Phenotypes ; Science & Technology ; Subgroups ; α‐GalA 3D‐structure</subject><ispartof>Journal of internal medicine, 2020-11, Vol.288 (5), p.593-604</ispartof><rights>2020 The Authors. published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine</rights><rights>2020 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.</rights><rights>2020. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>9</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000542593500001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c3935-eefa0489efba46b3a3710b4be61661159fa649219b5d5808465993281ce460073</citedby><cites>FETCH-LOGICAL-c3935-eefa0489efba46b3a3710b4be61661159fa649219b5d5808465993281ce460073</cites><orcidid>0000-0001-6973-6428</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjoim.13125$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fjoim.13125$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>315,782,786,1419,1435,27933,27934,28257,45583,45584,46418,46842</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32583479$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rickert, V.</creatorcontrib><creatorcontrib>Wagenhäuser, L.</creatorcontrib><creatorcontrib>Nordbeck, P.</creatorcontrib><creatorcontrib>Wanner, C.</creatorcontrib><creatorcontrib>Sommer, C.</creatorcontrib><creatorcontrib>Rost, S.</creatorcontrib><creatorcontrib>Üçeyler, N.</creatorcontrib><title>Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure</title><title>Journal of internal medicine</title><addtitle>J INTERN MED</addtitle><addtitle>J Intern Med</addtitle><description>Background
Fabry disease (FD) is an X‐linked lysosomal storage and multi‐system disorder due to mutations in the α‐galactosidase A (α‐GalA) gene. We investigated the impact of individual amino acid exchanges in the α‐GalA 3D‐structure on the clinical phenotype of FD patients.
Patients and methods
We enrolled 80 adult FD patients with α‐GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α‐GalA 3D‐structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD‐specific treatment.
Results
Patients with active site or buried mutations showed a severe phenotype with multi‐organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α‐GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso‐Gb3 levels were higher (P < 0.01 in men; <0.05 in women).
Conclusions
The type of amino acid exchange location in the α‐GalA 3D‐structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.</description><subject>alpha-Galactosidase - genetics</subject><subject>Amino acids</subject><subject>Buried structures</subject><subject>Exchanging</subject><subject>Fabry disease</subject><subject>Fabry Disease - complications</subject><subject>Fabry Disease - diagnosis</subject><subject>Fabry Disease - enzymology</subject><subject>Fabry Disease - genetics</subject><subject>Fabry genotype</subject><subject>Fabry phenotype</subject><subject>Fabry's disease</subject><subject>Galactosidase</subject><subject>General & Internal Medicine</subject><subject>Genotype & phenotype</subject><subject>Humans</subject><subject>Life Sciences & Biomedicine</subject><subject>lyso‐Gb3</subject><subject>Medicine, General & Internal</subject><subject>Missense mutation</subject><subject>Molecular Conformation</subject><subject>Mutation</subject><subject>Mutation, Missense</subject><subject>Parameters</subject><subject>Patients</subject><subject>Phenotypes</subject><subject>Science & Technology</subject><subject>Subgroups</subject><subject>α‐GalA 3D‐structure</subject><issn>0954-6820</issn><issn>1365-2796</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>AOWDO</sourceid><sourceid>EIF</sourceid><recordid>eNqNkU9u1DAYxS1ERacDGw6ALLFBrVL8PzG7aqC0qKgLYB05ni_IgxMPtiM0O47AVbgIh-hJcJuhCxYIL2zr6fc9PX0PoaeUnNJyXm6CG04pp0w-QAvKlaxYrdVDtCBaiko1jByio5Q2hFBOFHmEDjmTDRe1XiD_IUeTXe9sucOIQ4_PTRd3eJjynZKwG7H1biyEx9tobHYWXmFTxJAgYh_CF2wy_vXz5vuPz8YXICS3NgnwWVH4a5xynGyeIjxGB73xCZ7s3yX6dP7m4-qiurp-e7k6u6os11xWAL0hotHQd0aojhteU9KJDhRVilKpe6OEZlR3ci0b0gglteasoRaEIqTmS_Ri9t3G8HWClNvBJQvemxHClFomaC2I1EoU9Plf6CZMcSzpCiUZ43UxLtTxTNkYUorQt9voBhN3LSXtbQftbQftXQcFfra3nLoB1vfon6UX4GQGvkEX-mQdjBbuMUKIFEyWRZRfaWyJmv-nV25ubRWmMZdRuh91Hnb_yNy-u758P6f_DXlos3I</recordid><startdate>202011</startdate><enddate>202011</enddate><creator>Rickert, V.</creator><creator>Wagenhäuser, L.</creator><creator>Nordbeck, P.</creator><creator>Wanner, C.</creator><creator>Sommer, C.</creator><creator>Rost, S.</creator><creator>Üçeyler, N.</creator><general>Wiley</general><general>Blackwell Publishing Ltd</general><scope>24P</scope><scope>WIN</scope><scope>AOWDO</scope><scope>BLEPL</scope><scope>DTL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>C1K</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-6973-6428</orcidid></search><sort><creationdate>202011</creationdate><title>Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure</title><author>Rickert, V. ; Wagenhäuser, L. ; Nordbeck, P. ; Wanner, C. ; Sommer, C. ; Rost, S. ; Üçeyler, N.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3935-eefa0489efba46b3a3710b4be61661159fa649219b5d5808465993281ce460073</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>alpha-Galactosidase - genetics</topic><topic>Amino acids</topic><topic>Buried structures</topic><topic>Exchanging</topic><topic>Fabry disease</topic><topic>Fabry Disease - complications</topic><topic>Fabry Disease - diagnosis</topic><topic>Fabry Disease - enzymology</topic><topic>Fabry Disease - genetics</topic><topic>Fabry genotype</topic><topic>Fabry phenotype</topic><topic>Fabry's disease</topic><topic>Galactosidase</topic><topic>General & Internal Medicine</topic><topic>Genotype & phenotype</topic><topic>Humans</topic><topic>Life Sciences & Biomedicine</topic><topic>lyso‐Gb3</topic><topic>Medicine, General & Internal</topic><topic>Missense mutation</topic><topic>Molecular Conformation</topic><topic>Mutation</topic><topic>Mutation, Missense</topic><topic>Parameters</topic><topic>Patients</topic><topic>Phenotypes</topic><topic>Science & Technology</topic><topic>Subgroups</topic><topic>α‐GalA 3D‐structure</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rickert, V.</creatorcontrib><creatorcontrib>Wagenhäuser, L.</creatorcontrib><creatorcontrib>Nordbeck, P.</creatorcontrib><creatorcontrib>Wanner, C.</creatorcontrib><creatorcontrib>Sommer, C.</creatorcontrib><creatorcontrib>Rost, S.</creatorcontrib><creatorcontrib>Üçeyler, N.</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Web of Science - Science Citation Index Expanded - 2020</collection><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of internal medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rickert, V.</au><au>Wagenhäuser, L.</au><au>Nordbeck, P.</au><au>Wanner, C.</au><au>Sommer, C.</au><au>Rost, S.</au><au>Üçeyler, N.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure</atitle><jtitle>Journal of internal medicine</jtitle><stitle>J INTERN MED</stitle><addtitle>J Intern Med</addtitle><date>2020-11</date><risdate>2020</risdate><volume>288</volume><issue>5</issue><spage>593</spage><epage>604</epage><pages>593-604</pages><issn>0954-6820</issn><eissn>1365-2796</eissn><abstract>Background
Fabry disease (FD) is an X‐linked lysosomal storage and multi‐system disorder due to mutations in the α‐galactosidase A (α‐GalA) gene. We investigated the impact of individual amino acid exchanges in the α‐GalA 3D‐structure on the clinical phenotype of FD patients.
Patients and methods
We enrolled 80 adult FD patients with α‐GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α‐GalA 3D‐structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD‐specific treatment.
Results
Patients with active site or buried mutations showed a severe phenotype with multi‐organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α‐GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso‐Gb3 levels were higher (P < 0.01 in men; <0.05 in women).
Conclusions
The type of amino acid exchange location in the α‐GalA 3D‐structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.</abstract><cop>HOBOKEN</cop><pub>Wiley</pub><pmid>32583479</pmid><doi>10.1111/joim.13125</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-6973-6428</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0954-6820 |
| ispartof | Journal of internal medicine, 2020-11, Vol.288 (5), p.593-604 |
| issn | 0954-6820 1365-2796 |
| language | eng |
| recordid | cdi_pubmed_primary_32583479 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Access via Wiley Online Library; Web of Science - Science Citation Index Expanded - 2020<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; Wiley Online Library (Open Access Collection) |
| subjects | alpha-Galactosidase - genetics Amino acids Buried structures Exchanging Fabry disease Fabry Disease - complications Fabry Disease - diagnosis Fabry Disease - enzymology Fabry Disease - genetics Fabry genotype Fabry phenotype Fabry's disease Galactosidase General & Internal Medicine Genotype & phenotype Humans Life Sciences & Biomedicine lyso‐Gb3 Medicine, General & Internal Missense mutation Molecular Conformation Mutation Mutation, Missense Parameters Patients Phenotypes Science & Technology Subgroups α‐GalA 3D‐structure |
| title | Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-02T22%3A57%3A40IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Stratification%20of%20Fabry%20mutations%20in%20clinical%20practice:%20a%20closer%20look%20at%20%CE%B1%E2%80%90galactosidase%20A%E2%80%903D%20structure&rft.jtitle=Journal%20of%20internal%20medicine&rft.au=Rickert,%20V.&rft.date=2020-11&rft.volume=288&rft.issue=5&rft.spage=593&rft.epage=604&rft.pages=593-604&rft.issn=0954-6820&rft.eissn=1365-2796&rft_id=info:doi/10.1111/joim.13125&rft_dat=%3Cproquest_pubme%3E2417405964%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2452237328&rft_id=info:pmid/32583479&rfr_iscdi=true |