Functional rescue of misfolding ABCA3 mutations by small molecular correctors
Abstract Adenosine triphosphate (ATP)-binding cassette subfamily A member 3 (ABCA3), a phospholipid transporter in lung lamellar bodies (LBs), is essential for the assembly of pulmonary surfactant and LB biogenesis. Mutations in the ABCA3 gene are an important genetic cause for respiratory distress...
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| Veröffentlicht in: | Human molecular genetics 2018-03, Vol.27 (6), p.943-953 |
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| container_title | Human molecular genetics |
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| creator | Kinting, Susanna Höppner, Stefanie Schindlbeck, Ulrike Forstner, Maria E Harfst, Jacqueline Wittmann, Thomas Griese, Matthias |
| description | Abstract
Adenosine triphosphate (ATP)-binding cassette subfamily A member 3 (ABCA3), a phospholipid transporter in lung lamellar bodies (LBs), is essential for the assembly of pulmonary surfactant and LB biogenesis. Mutations in the ABCA3 gene are an important genetic cause for respiratory distress syndrome in neonates and interstitial lung disease in children and adults, for which there is currently no cure. The aim of this study was to prove that disease causing misfolding ABCA3 mutations can be corrected in vitro and to investigate available options for correction. We stably expressed hemagglutinin (HA)-tagged wild-type ABCA3 or variants p.Q215K, p.M760R, p.A1046E, p.K1388N or p.G1421R in A549 cells and assessed correction by quantitation of ABCA3 processing products, their intracellular localization, resembling LB morphological integrity and analysis of functional transport activity. We showed that all mutant proteins except for M760R ABCA3 were rescued by the bithiazole correctors C13 and C17. These variants were also corrected by the chemical chaperone trimethylamine N-oxide and by low temperature. The identification of lead molecules C13 and C17 is an important step toward pharmacotherapy of ABCA3 misfolding-induced lung disease. |
| doi_str_mv | 10.1093/hmg/ddy011 |
| format | Article |
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Adenosine triphosphate (ATP)-binding cassette subfamily A member 3 (ABCA3), a phospholipid transporter in lung lamellar bodies (LBs), is essential for the assembly of pulmonary surfactant and LB biogenesis. Mutations in the ABCA3 gene are an important genetic cause for respiratory distress syndrome in neonates and interstitial lung disease in children and adults, for which there is currently no cure. The aim of this study was to prove that disease causing misfolding ABCA3 mutations can be corrected in vitro and to investigate available options for correction. We stably expressed hemagglutinin (HA)-tagged wild-type ABCA3 or variants p.Q215K, p.M760R, p.A1046E, p.K1388N or p.G1421R in A549 cells and assessed correction by quantitation of ABCA3 processing products, their intracellular localization, resembling LB morphological integrity and analysis of functional transport activity. We showed that all mutant proteins except for M760R ABCA3 were rescued by the bithiazole correctors C13 and C17. These variants were also corrected by the chemical chaperone trimethylamine N-oxide and by low temperature. The identification of lead molecules C13 and C17 is an important step toward pharmacotherapy of ABCA3 misfolding-induced lung disease.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddy011</identifier><identifier>PMID: 29325094</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>A549 Cells ; ATP-Binding Cassette Transporters - genetics ; ATP-Binding Cassette Transporters - metabolism ; Humans ; Lung Diseases, Interstitial - drug therapy ; Lung Diseases, Interstitial - genetics ; Lung Diseases, Interstitial - metabolism ; Methylamines - pharmacology ; Molecular Chaperones - genetics ; Molecular Chaperones - metabolism ; Mutation, Missense - drug effects ; Proof of Concept Study ; Protein Folding ; Proteostasis Deficiencies - drug therapy ; Proteostasis Deficiencies - genetics ; Proteostasis Deficiencies - metabolism</subject><ispartof>Human molecular genetics, 2018-03, Vol.27 (6), p.943-953</ispartof><rights>The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-8c8e8971aa5716f94ffba37b23e9dc73447335447f08011fd45f4dfa64efb9e03</citedby><cites>FETCH-LOGICAL-c353t-8c8e8971aa5716f94ffba37b23e9dc73447335447f08011fd45f4dfa64efb9e03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1578,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29325094$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kinting, Susanna</creatorcontrib><creatorcontrib>Höppner, Stefanie</creatorcontrib><creatorcontrib>Schindlbeck, Ulrike</creatorcontrib><creatorcontrib>Forstner, Maria E</creatorcontrib><creatorcontrib>Harfst, Jacqueline</creatorcontrib><creatorcontrib>Wittmann, Thomas</creatorcontrib><creatorcontrib>Griese, Matthias</creatorcontrib><title>Functional rescue of misfolding ABCA3 mutations by small molecular correctors</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Abstract
Adenosine triphosphate (ATP)-binding cassette subfamily A member 3 (ABCA3), a phospholipid transporter in lung lamellar bodies (LBs), is essential for the assembly of pulmonary surfactant and LB biogenesis. Mutations in the ABCA3 gene are an important genetic cause for respiratory distress syndrome in neonates and interstitial lung disease in children and adults, for which there is currently no cure. The aim of this study was to prove that disease causing misfolding ABCA3 mutations can be corrected in vitro and to investigate available options for correction. We stably expressed hemagglutinin (HA)-tagged wild-type ABCA3 or variants p.Q215K, p.M760R, p.A1046E, p.K1388N or p.G1421R in A549 cells and assessed correction by quantitation of ABCA3 processing products, their intracellular localization, resembling LB morphological integrity and analysis of functional transport activity. We showed that all mutant proteins except for M760R ABCA3 were rescued by the bithiazole correctors C13 and C17. These variants were also corrected by the chemical chaperone trimethylamine N-oxide and by low temperature. The identification of lead molecules C13 and C17 is an important step toward pharmacotherapy of ABCA3 misfolding-induced lung disease.</description><subject>A549 Cells</subject><subject>ATP-Binding Cassette Transporters - genetics</subject><subject>ATP-Binding Cassette Transporters - metabolism</subject><subject>Humans</subject><subject>Lung Diseases, Interstitial - drug therapy</subject><subject>Lung Diseases, Interstitial - genetics</subject><subject>Lung Diseases, Interstitial - metabolism</subject><subject>Methylamines - pharmacology</subject><subject>Molecular Chaperones - genetics</subject><subject>Molecular Chaperones - metabolism</subject><subject>Mutation, Missense - drug effects</subject><subject>Proof of Concept Study</subject><subject>Protein Folding</subject><subject>Proteostasis Deficiencies - drug therapy</subject><subject>Proteostasis Deficiencies - genetics</subject><subject>Proteostasis Deficiencies - metabolism</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kD1PwzAQQC0EoqWw8AOQFySEFGrHjhOPbUUBqYgFZsvxRwly4mLHQ_89qVIYWe6Wp6e7B8A1Rg8YcTL_bLdzrfcI4xMwxZShLEcVOQVTxBnNGEdsAi5i_EIIM0rKczDJOckLxOkUvK5Tp_rGd9LBYKJKBnoL2yZa73TTbeFiuVoQ2KZeHqgI6z2MrXQOtt4ZlZwMUPkQjOp9iJfgzEoXzdVxz8DH-vF99Zxt3p5eVotNpkhB-qxSlal4iaUsSswsp9bWkpR1TgzXqiSUloQUw7SoGr6ymhaWaisZNbbmBpEZuBu9u-C_k4m9GC5WxjnZGZ-iwLziDFWU0wG9H1EVfIzBWLELTSvDXmAkDvnEkE-M-Qb45uhNdWv0H_rbawBuR8Cn3X-iHypxeIc</recordid><startdate>20180315</startdate><enddate>20180315</enddate><creator>Kinting, Susanna</creator><creator>Höppner, Stefanie</creator><creator>Schindlbeck, Ulrike</creator><creator>Forstner, Maria E</creator><creator>Harfst, Jacqueline</creator><creator>Wittmann, Thomas</creator><creator>Griese, Matthias</creator><general>Oxford University Press</general><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>7X8</scope></search><sort><creationdate>20180315</creationdate><title>Functional rescue of misfolding ABCA3 mutations by small molecular correctors</title><author>Kinting, Susanna ; Höppner, Stefanie ; Schindlbeck, Ulrike ; Forstner, Maria E ; Harfst, Jacqueline ; Wittmann, Thomas ; Griese, Matthias</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-8c8e8971aa5716f94ffba37b23e9dc73447335447f08011fd45f4dfa64efb9e03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>A549 Cells</topic><topic>ATP-Binding Cassette Transporters - genetics</topic><topic>ATP-Binding Cassette Transporters - metabolism</topic><topic>Humans</topic><topic>Lung Diseases, Interstitial - drug therapy</topic><topic>Lung Diseases, Interstitial - genetics</topic><topic>Lung Diseases, Interstitial - metabolism</topic><topic>Methylamines - pharmacology</topic><topic>Molecular Chaperones - genetics</topic><topic>Molecular Chaperones - metabolism</topic><topic>Mutation, Missense - drug effects</topic><topic>Proof of Concept Study</topic><topic>Protein Folding</topic><topic>Proteostasis Deficiencies - drug therapy</topic><topic>Proteostasis Deficiencies - genetics</topic><topic>Proteostasis Deficiencies - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kinting, Susanna</creatorcontrib><creatorcontrib>Höppner, Stefanie</creatorcontrib><creatorcontrib>Schindlbeck, Ulrike</creatorcontrib><creatorcontrib>Forstner, Maria E</creatorcontrib><creatorcontrib>Harfst, Jacqueline</creatorcontrib><creatorcontrib>Wittmann, Thomas</creatorcontrib><creatorcontrib>Griese, Matthias</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kinting, Susanna</au><au>Höppner, Stefanie</au><au>Schindlbeck, Ulrike</au><au>Forstner, Maria E</au><au>Harfst, Jacqueline</au><au>Wittmann, Thomas</au><au>Griese, Matthias</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Functional rescue of misfolding ABCA3 mutations by small molecular correctors</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2018-03-15</date><risdate>2018</risdate><volume>27</volume><issue>6</issue><spage>943</spage><epage>953</epage><pages>943-953</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><abstract>Abstract
Adenosine triphosphate (ATP)-binding cassette subfamily A member 3 (ABCA3), a phospholipid transporter in lung lamellar bodies (LBs), is essential for the assembly of pulmonary surfactant and LB biogenesis. Mutations in the ABCA3 gene are an important genetic cause for respiratory distress syndrome in neonates and interstitial lung disease in children and adults, for which there is currently no cure. The aim of this study was to prove that disease causing misfolding ABCA3 mutations can be corrected in vitro and to investigate available options for correction. We stably expressed hemagglutinin (HA)-tagged wild-type ABCA3 or variants p.Q215K, p.M760R, p.A1046E, p.K1388N or p.G1421R in A549 cells and assessed correction by quantitation of ABCA3 processing products, their intracellular localization, resembling LB morphological integrity and analysis of functional transport activity. We showed that all mutant proteins except for M760R ABCA3 were rescued by the bithiazole correctors C13 and C17. These variants were also corrected by the chemical chaperone trimethylamine N-oxide and by low temperature. The identification of lead molecules C13 and C17 is an important step toward pharmacotherapy of ABCA3 misfolding-induced lung disease.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>29325094</pmid><doi>10.1093/hmg/ddy011</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | A549 Cells ATP-Binding Cassette Transporters - genetics ATP-Binding Cassette Transporters - metabolism Humans Lung Diseases, Interstitial - drug therapy Lung Diseases, Interstitial - genetics Lung Diseases, Interstitial - metabolism Methylamines - pharmacology Molecular Chaperones - genetics Molecular Chaperones - metabolism Mutation, Missense - drug effects Proof of Concept Study Protein Folding Proteostasis Deficiencies - drug therapy Proteostasis Deficiencies - genetics Proteostasis Deficiencies - metabolism |
| title | Functional rescue of misfolding ABCA3 mutations by small molecular correctors |
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