Novel ATPase Cu2+ Transporting Beta Polypeptide Mutations in Chinese Families with Wilson's Disease
Wilson's disease (WD) is an autosomal recessive inherited disorder caused by mutations in the ATPase Cu2+ transporting beta polypeptide gene (ATP7B). The detailed metabolism of copper-induced pathology in WD is still unknown. Gene mutations as well as the possible pathways involved in the ATP7B...
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| Veröffentlicht in: | PloS one 2013-07, Vol.8 (7), p.e66526 |
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| description | Wilson's disease (WD) is an autosomal recessive inherited disorder caused by mutations in the ATPase Cu2+ transporting beta polypeptide gene (ATP7B). The detailed metabolism of copper-induced pathology in WD is still unknown. Gene mutations as well as the possible pathways involved in the ATP7B deficiency were documented. The ATP7B gene was analyzed for mutations in 18 Chinese Han families with WD by direct sequencing. Cell viability and apoptosis analysis of ATP7B small interfering RNA (siRNA)-treated human liver carcinoma (HepG2) cells were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst 33342 staining. Finally, the expression of B-cell CLL/lymphoma 2 (BCL2), BCL2-associated X protein (BAX), sterol regulatory element binding protein 1 (SREBP1), and minichromosome maintenance protein 7 (MCM7) of ATP7B siRNA-treated cells were tested by real-time polymerase chain reaction (real-time PCR) and Western blot analysis. Twenty different mutations including four novel mutations (p.Val145Phe, p.Glu388X, p.Thr498Ser and p.Gly837X) in the ATP7B gene were identified in our families. Haplotype analysis revealed that founder effects for four mutations (p.Arg778Leu, p.Pro992Leu, p.Ile1148Thr and p.Ala1295Val) existed in these families. Transfection of HepG2 cells with ATP7B siRNA resulted in decreased mRNA expression by 86.3%, 93.1% and 90.8%, and decreased protein levels by 58.5%, 85.5% and 82.1% at 24, 48 and 72 hours, respectively (All P |
| doi_str_mv | 10.1371/journal.pone.0066526 |
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The detailed metabolism of copper-induced pathology in WD is still unknown. Gene mutations as well as the possible pathways involved in the ATP7B deficiency were documented. The ATP7B gene was analyzed for mutations in 18 Chinese Han families with WD by direct sequencing. Cell viability and apoptosis analysis of ATP7B small interfering RNA (siRNA)-treated human liver carcinoma (HepG2) cells were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst 33342 staining. Finally, the expression of B-cell CLL/lymphoma 2 (BCL2), BCL2-associated X protein (BAX), sterol regulatory element binding protein 1 (SREBP1), and minichromosome maintenance protein 7 (MCM7) of ATP7B siRNA-treated cells were tested by real-time polymerase chain reaction (real-time PCR) and Western blot analysis. Twenty different mutations including four novel mutations (p.Val145Phe, p.Glu388X, p.Thr498Ser and p.Gly837X) in the ATP7B gene were identified in our families. Haplotype analysis revealed that founder effects for four mutations (p.Arg778Leu, p.Pro992Leu, p.Ile1148Thr and p.Ala1295Val) existed in these families. Transfection of HepG2 cells with ATP7B siRNA resulted in decreased mRNA expression by 86.3%, 93.1% and 90.8%, and decreased protein levels by 58.5%, 85.5% and 82.1% at 24, 48 and 72 hours, respectively (All P<0.01). In vitro study revealed that the apoptotic, cell cycle and lipid metabolism pathway may be involved in the mechanism of WD. Our results revealed that the genetic cause of 18 Chinese families with WD and ATP7B deficiency-induce apoptosis may result from imbalance in cell cycle and lipid metabolism pathway.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0066526</identifier><identifier>PMID: 23843956</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Adenosine triphosphatase ; Alzheimer's disease ; Alzheimers disease ; Apoptosis ; ATP7B gene ; BAX protein ; Bcl-2 protein ; Bcl-x protein ; Biology ; Cell cycle ; Chronic lymphatic leukemia ; Chronic lymphocytic leukemia ; Copper ; Family medical history ; Gene expression ; Gene sequencing ; Haplotypes ; Hepatocytes ; Hereditary diseases ; Hospitals ; Lipid metabolism ; Liver ; Liver diseases ; Lymphocytes B ; Lymphoma ; Mathematics ; Medicine ; Metabolism ; Mutation ; Neurology ; Polymerase chain reaction ; Polypeptides ; Real time ; Ribonucleic acid ; RNA ; siRNA ; Sterol regulatory element-binding protein ; Transfection ; Transportation ; Wilson's disease ; X protein</subject><ispartof>PloS one, 2013-07, Vol.8 (7), p.e66526</ispartof><rights>2013 Gu 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>2013 Gu et al 2013 Gu et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c334t-b9e962b6a9affc02119cf7af054f24e825b091614471113915ab1339059235883</citedby><cites>FETCH-LOGICAL-c334t-b9e962b6a9affc02119cf7af054f24e825b091614471113915ab1339059235883</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/PMC3699604/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699604/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids></links><search><contributor>Avila, Matias A.</contributor><creatorcontrib>Gu, Shaojuan</creatorcontrib><creatorcontrib>Yang, Huarong</creatorcontrib><creatorcontrib>Qi, Yong</creatorcontrib><creatorcontrib>Deng, Xiong</creatorcontrib><creatorcontrib>Zhang, Le</creatorcontrib><creatorcontrib>Guo, Yi</creatorcontrib><creatorcontrib>Huang, Qing</creatorcontrib><creatorcontrib>Li, Jing</creatorcontrib><creatorcontrib>Shi, Xiaoliu</creatorcontrib><creatorcontrib>Song, Zhi</creatorcontrib><creatorcontrib>Deng, Hao</creatorcontrib><title>Novel ATPase Cu2+ Transporting Beta Polypeptide Mutations in Chinese Families with Wilson's Disease</title><title>PloS one</title><description>Wilson's disease (WD) is an autosomal recessive inherited disorder caused by mutations in the ATPase Cu2+ transporting beta polypeptide gene (ATP7B). The detailed metabolism of copper-induced pathology in WD is still unknown. Gene mutations as well as the possible pathways involved in the ATP7B deficiency were documented. The ATP7B gene was analyzed for mutations in 18 Chinese Han families with WD by direct sequencing. Cell viability and apoptosis analysis of ATP7B small interfering RNA (siRNA)-treated human liver carcinoma (HepG2) cells were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst 33342 staining. Finally, the expression of B-cell CLL/lymphoma 2 (BCL2), BCL2-associated X protein (BAX), sterol regulatory element binding protein 1 (SREBP1), and minichromosome maintenance protein 7 (MCM7) of ATP7B siRNA-treated cells were tested by real-time polymerase chain reaction (real-time PCR) and Western blot analysis. Twenty different mutations including four novel mutations (p.Val145Phe, p.Glu388X, p.Thr498Ser and p.Gly837X) in the ATP7B gene were identified in our families. Haplotype analysis revealed that founder effects for four mutations (p.Arg778Leu, p.Pro992Leu, p.Ile1148Thr and p.Ala1295Val) existed in these families. Transfection of HepG2 cells with ATP7B siRNA resulted in decreased mRNA expression by 86.3%, 93.1% and 90.8%, and decreased protein levels by 58.5%, 85.5% and 82.1% at 24, 48 and 72 hours, respectively (All P<0.01). In vitro study revealed that the apoptotic, cell cycle and lipid metabolism pathway may be involved in the mechanism of WD. Our results revealed that the genetic cause of 18 Chinese families with WD and ATP7B deficiency-induce apoptosis may result from imbalance in cell cycle and lipid metabolism pathway.</description><subject>Adenosine triphosphatase</subject><subject>Alzheimer's disease</subject><subject>Alzheimers disease</subject><subject>Apoptosis</subject><subject>ATP7B gene</subject><subject>BAX protein</subject><subject>Bcl-2 protein</subject><subject>Bcl-x protein</subject><subject>Biology</subject><subject>Cell cycle</subject><subject>Chronic lymphatic leukemia</subject><subject>Chronic lymphocytic leukemia</subject><subject>Copper</subject><subject>Family medical history</subject><subject>Gene expression</subject><subject>Gene sequencing</subject><subject>Haplotypes</subject><subject>Hepatocytes</subject><subject>Hereditary diseases</subject><subject>Hospitals</subject><subject>Lipid metabolism</subject><subject>Liver</subject><subject>Liver diseases</subject><subject>Lymphocytes B</subject><subject>Lymphoma</subject><subject>Mathematics</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Mutation</subject><subject>Neurology</subject><subject>Polymerase chain reaction</subject><subject>Polypeptides</subject><subject>Real time</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>siRNA</subject><subject>Sterol regulatory element-binding protein</subject><subject>Transfection</subject><subject>Transportation</subject><subject>Wilson's disease</subject><subject>X 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ATPase Cu2+ Transporting Beta Polypeptide Mutations in Chinese Families with Wilson's Disease</title><author>Gu, Shaojuan ; Yang, Huarong ; Qi, Yong ; Deng, Xiong ; Zhang, Le ; Guo, Yi ; Huang, Qing ; Li, Jing ; Shi, Xiaoliu ; Song, Zhi ; Deng, Hao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c334t-b9e962b6a9affc02119cf7af054f24e825b091614471113915ab1339059235883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adenosine triphosphatase</topic><topic>Alzheimer's disease</topic><topic>Alzheimers disease</topic><topic>Apoptosis</topic><topic>ATP7B gene</topic><topic>BAX protein</topic><topic>Bcl-2 protein</topic><topic>Bcl-x protein</topic><topic>Biology</topic><topic>Cell cycle</topic><topic>Chronic lymphatic leukemia</topic><topic>Chronic lymphocytic leukemia</topic><topic>Copper</topic><topic>Family medical history</topic><topic>Gene expression</topic><topic>Gene 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Transporting Beta Polypeptide Mutations in Chinese Families with Wilson's Disease</atitle><jtitle>PloS one</jtitle><date>2013-07-02</date><risdate>2013</risdate><volume>8</volume><issue>7</issue><spage>e66526</spage><pages>e66526-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Wilson's disease (WD) is an autosomal recessive inherited disorder caused by mutations in the ATPase Cu2+ transporting beta polypeptide gene (ATP7B). The detailed metabolism of copper-induced pathology in WD is still unknown. Gene mutations as well as the possible pathways involved in the ATP7B deficiency were documented. The ATP7B gene was analyzed for mutations in 18 Chinese Han families with WD by direct sequencing. Cell viability and apoptosis analysis of ATP7B small interfering RNA (siRNA)-treated human liver carcinoma (HepG2) cells were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst 33342 staining. Finally, the expression of B-cell CLL/lymphoma 2 (BCL2), BCL2-associated X protein (BAX), sterol regulatory element binding protein 1 (SREBP1), and minichromosome maintenance protein 7 (MCM7) of ATP7B siRNA-treated cells were tested by real-time polymerase chain reaction (real-time PCR) and Western blot analysis. Twenty different mutations including four novel mutations (p.Val145Phe, p.Glu388X, p.Thr498Ser and p.Gly837X) in the ATP7B gene were identified in our families. Haplotype analysis revealed that founder effects for four mutations (p.Arg778Leu, p.Pro992Leu, p.Ile1148Thr and p.Ala1295Val) existed in these families. Transfection of HepG2 cells with ATP7B siRNA resulted in decreased mRNA expression by 86.3%, 93.1% and 90.8%, and decreased protein levels by 58.5%, 85.5% and 82.1% at 24, 48 and 72 hours, respectively (All P<0.01). In vitro study revealed that the apoptotic, cell cycle and lipid metabolism pathway may be involved in the mechanism of WD. Our results revealed that the genetic cause of 18 Chinese families with WD and ATP7B deficiency-induce apoptosis may result from imbalance in cell cycle and lipid metabolism pathway.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>23843956</pmid><doi>10.1371/journal.pone.0066526</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Adenosine triphosphatase Alzheimer's disease Alzheimers disease Apoptosis ATP7B gene BAX protein Bcl-2 protein Bcl-x protein Biology Cell cycle Chronic lymphatic leukemia Chronic lymphocytic leukemia Copper Family medical history Gene expression Gene sequencing Haplotypes Hepatocytes Hereditary diseases Hospitals Lipid metabolism Liver Liver diseases Lymphocytes B Lymphoma Mathematics Medicine Metabolism Mutation Neurology Polymerase chain reaction Polypeptides Real time Ribonucleic acid RNA siRNA Sterol regulatory element-binding protein Transfection Transportation Wilson's disease X protein |
| title | Novel ATPase Cu2+ Transporting Beta Polypeptide Mutations in Chinese Families with Wilson's Disease |
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