Expression and in vivo rescue of human ABCC6 disease-causing mutants in mouse liver
Loss-of-function mutations in ABCC6 can cause chronic or acute forms of dystrophic mineralization described in disease models such as pseudoxanthoma elasticum (OMIM 26480) in human and dystrophic cardiac calcification in mice. The ABCC6 protein is a large membrane-embedded organic anion transporter...
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creator | Le Saux, Olivier Fülöp, Krisztina Yamaguchi, Yukiko Iliás, Attila Szabó, Zalán Brampton, Christopher N Pomozi, Viola Huszár, Krisztina Arányi, Tamás Váradi, András |
description | Loss-of-function mutations in ABCC6 can cause chronic or acute forms of dystrophic mineralization described in disease models such as pseudoxanthoma elasticum (OMIM 26480) in human and dystrophic cardiac calcification in mice. The ABCC6 protein is a large membrane-embedded organic anion transporter primarily found in the plasma membrane of hepatocytes. We have established a complex experimental strategy to determine the structural and functional consequences of disease-causing mutations in the human ABCC6. The major aim of our study was to identify mutants with preserved transport activity but failure in intracellular targeting. Five missense mutations were investigated: R1138Q, V1298F, R1314W, G1321S and R1339C. Using in vitro assays, we have identified two variants; R1138Q and R1314W that retained significant transport activity. All mutants were transiently expressed in vivo, in mouse liver via hydrodynamic tail vein injections. The inactive V1298F was the only mutant that showed normal cellular localization in liver hepatocytes while the other mutants showed mostly intracellular accumulation indicating abnormal trafficking. As both R1138Q and R1314W displayed endoplasmic reticulum localization, we tested whether 4-phenylbutyrate (4-PBA), a drug approved for clinical use, could restore their intracellular trafficking to the plasma membrane in MDCKII and mouse liver. The cellular localization of R1314W was significantly improved by 4-PBA treatment, thus potentially rescuing its physiological function. Our work demonstrates the feasibility of the in vivo rescue of cellular maturation of some ABCC6 mutants in physiological conditions very similar to the biology of the fully differentiated human liver and could have future human therapeutic application. |
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The ABCC6 protein is a large membrane-embedded organic anion transporter primarily found in the plasma membrane of hepatocytes. We have established a complex experimental strategy to determine the structural and functional consequences of disease-causing mutations in the human ABCC6. The major aim of our study was to identify mutants with preserved transport activity but failure in intracellular targeting. Five missense mutations were investigated: R1138Q, V1298F, R1314W, G1321S and R1339C. Using in vitro assays, we have identified two variants; R1138Q and R1314W that retained significant transport activity. All mutants were transiently expressed in vivo, in mouse liver via hydrodynamic tail vein injections. The inactive V1298F was the only mutant that showed normal cellular localization in liver hepatocytes while the other mutants showed mostly intracellular accumulation indicating abnormal trafficking. As both R1138Q and R1314W displayed endoplasmic reticulum localization, we tested whether 4-phenylbutyrate (4-PBA), a drug approved for clinical use, could restore their intracellular trafficking to the plasma membrane in MDCKII and mouse liver. The cellular localization of R1314W was significantly improved by 4-PBA treatment, thus potentially rescuing its physiological function. Our work demonstrates the feasibility of the in vivo rescue of cellular maturation of some ABCC6 mutants in physiological conditions very similar to the biology of the fully differentiated human liver and could have future human therapeutic application.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0024738</identifier><identifier>PMID: 21935449</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animal models ; Animals ; Biological Transport - genetics ; Biological Transport - physiology ; Biology ; Calcification ; Calcification (ectopic) ; Cystic fibrosis ; Deoxyribonucleic acid ; Disease ; DNA ; Endoplasmic reticulum ; Feasibility studies ; Gene expression ; Heart diseases ; Hepatocytes ; Humans ; Intracellular ; Liver ; Liver - metabolism ; Liver - pathology ; Localization ; Medicine ; Membrane proteins ; Membrane trafficking ; Mice ; Mice, Transgenic ; Mineralization ; Missense mutation ; Molecular biology ; Multidrug Resistance-Associated Proteins - genetics ; Multidrug Resistance-Associated Proteins - metabolism ; Mutants ; Mutation ; Phenylbutyric acid ; Physiological aspects ; Physiology ; Proteins ; Rodents ; Structure-function relationships ; Transport ; Veins & arteries</subject><ispartof>PloS one, 2011-09, Vol.6 (9), p.e24738-e24738</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Le Saux et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Le Saux et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c757t-464a9d012795ceeec4e8267dbf210a85fb556d1b8cbc30203e71dc2887a514303</citedby><cites>FETCH-LOGICAL-c757t-464a9d012795ceeec4e8267dbf210a85fb556d1b8cbc30203e71dc2887a514303</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173462/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173462/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2104,2930,23873,27931,27932,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21935449$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Uversky, Vladimir N.</contributor><creatorcontrib>Le Saux, Olivier</creatorcontrib><creatorcontrib>Fülöp, Krisztina</creatorcontrib><creatorcontrib>Yamaguchi, Yukiko</creatorcontrib><creatorcontrib>Iliás, Attila</creatorcontrib><creatorcontrib>Szabó, Zalán</creatorcontrib><creatorcontrib>Brampton, Christopher N</creatorcontrib><creatorcontrib>Pomozi, Viola</creatorcontrib><creatorcontrib>Huszár, Krisztina</creatorcontrib><creatorcontrib>Arányi, Tamás</creatorcontrib><creatorcontrib>Váradi, András</creatorcontrib><title>Expression and in vivo rescue of human ABCC6 disease-causing mutants in mouse liver</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Loss-of-function mutations in ABCC6 can cause chronic or acute forms of dystrophic mineralization described in disease models such as pseudoxanthoma elasticum (OMIM 26480) in human and dystrophic cardiac calcification in mice. 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As both R1138Q and R1314W displayed endoplasmic reticulum localization, we tested whether 4-phenylbutyrate (4-PBA), a drug approved for clinical use, could restore their intracellular trafficking to the plasma membrane in MDCKII and mouse liver. The cellular localization of R1314W was significantly improved by 4-PBA treatment, thus potentially rescuing its physiological function. 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The ABCC6 protein is a large membrane-embedded organic anion transporter primarily found in the plasma membrane of hepatocytes. We have established a complex experimental strategy to determine the structural and functional consequences of disease-causing mutations in the human ABCC6. The major aim of our study was to identify mutants with preserved transport activity but failure in intracellular targeting. Five missense mutations were investigated: R1138Q, V1298F, R1314W, G1321S and R1339C. Using in vitro assays, we have identified two variants; R1138Q and R1314W that retained significant transport activity. All mutants were transiently expressed in vivo, in mouse liver via hydrodynamic tail vein injections. The inactive V1298F was the only mutant that showed normal cellular localization in liver hepatocytes while the other mutants showed mostly intracellular accumulation indicating abnormal trafficking. As both R1138Q and R1314W displayed endoplasmic reticulum localization, we tested whether 4-phenylbutyrate (4-PBA), a drug approved for clinical use, could restore their intracellular trafficking to the plasma membrane in MDCKII and mouse liver. The cellular localization of R1314W was significantly improved by 4-PBA treatment, thus potentially rescuing its physiological function. Our work demonstrates the feasibility of the in vivo rescue of cellular maturation of some ABCC6 mutants in physiological conditions very similar to the biology of the fully differentiated human liver and could have future human therapeutic application.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21935449</pmid><doi>10.1371/journal.pone.0024738</doi><tpages>e24738</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animal models Animals Biological Transport - genetics Biological Transport - physiology Biology Calcification Calcification (ectopic) Cystic fibrosis Deoxyribonucleic acid Disease DNA Endoplasmic reticulum Feasibility studies Gene expression Heart diseases Hepatocytes Humans Intracellular Liver Liver - metabolism Liver - pathology Localization Medicine Membrane proteins Membrane trafficking Mice Mice, Transgenic Mineralization Missense mutation Molecular biology Multidrug Resistance-Associated Proteins - genetics Multidrug Resistance-Associated Proteins - metabolism Mutants Mutation Phenylbutyric acid Physiological aspects Physiology Proteins Rodents Structure-function relationships Transport Veins & arteries |
title | Expression and in vivo rescue of human ABCC6 disease-causing mutants in mouse liver |
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