CSB-PGBD3 Mutations Cause Premature Ovarian Failure
Premature ovarian failure (POF) is a rare, heterogeneous disorder characterized by cessation of menstruation occurring before the age of 40 years. Genetic etiology is responsible for perhaps 25% of cases, but most cases are sporadic and unexplained. In this study, through whole exome sequencing in a...
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| Veröffentlicht in: | PLoS genetics 2015-07, Vol.11 (7), p.e1005419-e1005419 |
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| creator | Qin, Yingying Guo, Ting Li, Guangyu Tang, Tie-Shan Zhao, Shidou Jiao, Xue Gong, Juanjuan Gao, Fei Guo, Caixia Simpson, Joe Leigh Chen, Zi-Jiang |
| description | Premature ovarian failure (POF) is a rare, heterogeneous disorder characterized by cessation of menstruation occurring before the age of 40 years. Genetic etiology is responsible for perhaps 25% of cases, but most cases are sporadic and unexplained. In this study, through whole exome sequencing in a non-consanguineous family having four affected members with POF and Sanger sequencing in 432 sporadic cases, we identified three novel mutations in the fusion gene CSB-PGBD3. Subsequently functional studies suggest that mutated CSB-PGBD3 fusion protein was impaired in response to DNA damage, as indicated by delayed or absent recruitment to damaged sites. Our data provide the first evidence that mutations in the CSB-PGBD3 fusion protein can cause human disease, even in the presence of functional CSB, thus potentially explaining conservation of the fusion protein for 43 My since marmoset. The localization of the CSB-PGBD3 fusion protein to UVA-induced nuclear DNA repair foci further suggests that the CSB-PGBD3 fusion protein, like many other proteins that can cause POF, modulates or participates in DNA repair. |
| doi_str_mv | 10.1371/journal.pgen.1005419 |
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Genetic etiology is responsible for perhaps 25% of cases, but most cases are sporadic and unexplained. In this study, through whole exome sequencing in a non-consanguineous family having four affected members with POF and Sanger sequencing in 432 sporadic cases, we identified three novel mutations in the fusion gene CSB-PGBD3. Subsequently functional studies suggest that mutated CSB-PGBD3 fusion protein was impaired in response to DNA damage, as indicated by delayed or absent recruitment to damaged sites. Our data provide the first evidence that mutations in the CSB-PGBD3 fusion protein can cause human disease, even in the presence of functional CSB, thus potentially explaining conservation of the fusion protein for 43 My since marmoset. The localization of the CSB-PGBD3 fusion protein to UVA-induced nuclear DNA repair foci further suggests that the CSB-PGBD3 fusion protein, like many other proteins that can cause POF, modulates or participates in DNA repair.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1005419</identifier><identifier>PMID: 26218421</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Age ; Aged ; Base Sequence ; Cell Line, Tumor ; Cloning ; Cockayne Syndrome - genetics ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA Damage - genetics ; DNA Helicases - genetics ; DNA repair ; DNA Repair - genetics ; DNA Repair Enzymes - genetics ; Female ; Genes ; Genomes ; HEK293 Cells ; HeLa Cells ; Humans ; Menopause, Premature - genetics ; Middle Aged ; Mutagenesis ; Mutant Chimeric Proteins - genetics ; Mutation ; Poly-ADP-Ribose Binding Proteins ; Primary Ovarian Insufficiency - genetics ; Proteins ; Recombinant Fusion Proteins - genetics ; RNA polymerase ; Sequence Analysis, DNA ; Studies</subject><ispartof>PLoS genetics, 2015-07, Vol.11 (7), p.e1005419-e1005419</ispartof><rights>2015 Qin et al 2015 Qin et al</rights><rights>2015 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Qin Y, Guo T, Li G, Tang T-S, Zhao S, Jiao X, et al. (2015) CSB-PGBD3 Mutations Cause Premature Ovarian Failure. 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Genetic etiology is responsible for perhaps 25% of cases, but most cases are sporadic and unexplained. In this study, through whole exome sequencing in a non-consanguineous family having four affected members with POF and Sanger sequencing in 432 sporadic cases, we identified three novel mutations in the fusion gene CSB-PGBD3. Subsequently functional studies suggest that mutated CSB-PGBD3 fusion protein was impaired in response to DNA damage, as indicated by delayed or absent recruitment to damaged sites. Our data provide the first evidence that mutations in the CSB-PGBD3 fusion protein can cause human disease, even in the presence of functional CSB, thus potentially explaining conservation of the fusion protein for 43 My since marmoset. The localization of the CSB-PGBD3 fusion protein to UVA-induced nuclear DNA repair foci further suggests that the CSB-PGBD3 fusion protein, like many other proteins that can cause POF, modulates or participates in DNA repair.</description><subject>Adult</subject><subject>Age</subject><subject>Aged</subject><subject>Base Sequence</subject><subject>Cell Line, Tumor</subject><subject>Cloning</subject><subject>Cockayne Syndrome - genetics</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA Damage - genetics</subject><subject>DNA Helicases - genetics</subject><subject>DNA repair</subject><subject>DNA Repair - genetics</subject><subject>DNA Repair Enzymes - genetics</subject><subject>Female</subject><subject>Genes</subject><subject>Genomes</subject><subject>HEK293 Cells</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Menopause, Premature - genetics</subject><subject>Middle Aged</subject><subject>Mutagenesis</subject><subject>Mutant Chimeric Proteins - genetics</subject><subject>Mutation</subject><subject>Poly-ADP-Ribose Binding Proteins</subject><subject>Primary Ovarian Insufficiency - genetics</subject><subject>Proteins</subject><subject>Recombinant Fusion Proteins - genetics</subject><subject>RNA polymerase</subject><subject>Sequence Analysis, DNA</subject><subject>Studies</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNpVkV1P2zAUhq1p02DAP5i2XHKTzscfsX0zaXS0QwK1EnBtnSR2lyqNOztB2r8n0IDgxp_vec579BLyFegMuIIf2zDEDtvZfuO6GVAqBZgP5Bik5LkSVHx8cz4iX1LaUsqlNuozOWIFAy0YHBM-v73I18uL3zy7GXrsm9ClbI5Dctk6uh32Q3TZ6gFjg122wKYd76fkk8c2ubNpPyH3i8u7-Z_8erW8mv-6zithdJ-j54UGbdAoZ2qtKPgadSlEVUilgIGRpeSjRyNpKQyysjYIIOvCMW-k5yfk-4G7b0Oy07zJgqJaMl1QOSquDoo64NbuY7PD-N8GbOzzQ4gbi7FvqtZZAFp5LY33KEXhqTHSIWOcaig4VHRk_Zy6DeXO1ZXr-ojtO-j7n675azfhwQoJSik9As4nQAz_Bpd6u2tS5doWOxeGZ9-U83E1o1QcpFUMKUXnX9sAtU_pvkxrn9K1U7pj2be3Fl-LXuLkjyt0oEQ</recordid><startdate>20150701</startdate><enddate>20150701</enddate><creator>Qin, Yingying</creator><creator>Guo, Ting</creator><creator>Li, Guangyu</creator><creator>Tang, Tie-Shan</creator><creator>Zhao, Shidou</creator><creator>Jiao, Xue</creator><creator>Gong, Juanjuan</creator><creator>Gao, Fei</creator><creator>Guo, Caixia</creator><creator>Simpson, Joe Leigh</creator><creator>Chen, Zi-Jiang</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150701</creationdate><title>CSB-PGBD3 Mutations Cause Premature Ovarian Failure</title><author>Qin, Yingying ; Guo, Ting ; Li, Guangyu ; Tang, Tie-Shan ; Zhao, Shidou ; Jiao, Xue ; Gong, Juanjuan ; Gao, Fei ; Guo, Caixia ; Simpson, Joe Leigh ; Chen, Zi-Jiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c498t-af368189a97e9d8701fda8b44c657712195b53155950b49a2bd9a115d6e2f95f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adult</topic><topic>Age</topic><topic>Aged</topic><topic>Base Sequence</topic><topic>Cell Line, Tumor</topic><topic>Cloning</topic><topic>Cockayne Syndrome - genetics</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA Damage - genetics</topic><topic>DNA Helicases - genetics</topic><topic>DNA repair</topic><topic>DNA Repair - genetics</topic><topic>DNA Repair Enzymes - genetics</topic><topic>Female</topic><topic>Genes</topic><topic>Genomes</topic><topic>HEK293 Cells</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Menopause, Premature - genetics</topic><topic>Middle Aged</topic><topic>Mutagenesis</topic><topic>Mutant Chimeric Proteins - genetics</topic><topic>Mutation</topic><topic>Poly-ADP-Ribose Binding Proteins</topic><topic>Primary Ovarian Insufficiency - genetics</topic><topic>Proteins</topic><topic>Recombinant Fusion Proteins - genetics</topic><topic>RNA polymerase</topic><topic>Sequence Analysis, DNA</topic><topic>Studies</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Qin, Yingying</creatorcontrib><creatorcontrib>Guo, Ting</creatorcontrib><creatorcontrib>Li, Guangyu</creatorcontrib><creatorcontrib>Tang, Tie-Shan</creatorcontrib><creatorcontrib>Zhao, Shidou</creatorcontrib><creatorcontrib>Jiao, Xue</creatorcontrib><creatorcontrib>Gong, Juanjuan</creatorcontrib><creatorcontrib>Gao, Fei</creatorcontrib><creatorcontrib>Guo, Caixia</creatorcontrib><creatorcontrib>Simpson, Joe Leigh</creatorcontrib><creatorcontrib>Chen, Zi-Jiang</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><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Qin, Yingying</au><au>Guo, Ting</au><au>Li, Guangyu</au><au>Tang, Tie-Shan</au><au>Zhao, Shidou</au><au>Jiao, Xue</au><au>Gong, Juanjuan</au><au>Gao, Fei</au><au>Guo, Caixia</au><au>Simpson, Joe Leigh</au><au>Chen, Zi-Jiang</au><au>Ford, James M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CSB-PGBD3 Mutations Cause Premature Ovarian Failure</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2015-07-01</date><risdate>2015</risdate><volume>11</volume><issue>7</issue><spage>e1005419</spage><epage>e1005419</epage><pages>e1005419-e1005419</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>Premature ovarian failure (POF) is a rare, heterogeneous disorder characterized by cessation of menstruation occurring before the age of 40 years. Genetic etiology is responsible for perhaps 25% of cases, but most cases are sporadic and unexplained. In this study, through whole exome sequencing in a non-consanguineous family having four affected members with POF and Sanger sequencing in 432 sporadic cases, we identified three novel mutations in the fusion gene CSB-PGBD3. Subsequently functional studies suggest that mutated CSB-PGBD3 fusion protein was impaired in response to DNA damage, as indicated by delayed or absent recruitment to damaged sites. Our data provide the first evidence that mutations in the CSB-PGBD3 fusion protein can cause human disease, even in the presence of functional CSB, thus potentially explaining conservation of the fusion protein for 43 My since marmoset. The localization of the CSB-PGBD3 fusion protein to UVA-induced nuclear DNA repair foci further suggests that the CSB-PGBD3 fusion protein, like many other proteins that can cause POF, modulates or participates in DNA repair.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26218421</pmid><doi>10.1371/journal.pgen.1005419</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Age Aged Base Sequence Cell Line, Tumor Cloning Cockayne Syndrome - genetics Deoxyribonucleic acid DNA DNA damage DNA Damage - genetics DNA Helicases - genetics DNA repair DNA Repair - genetics DNA Repair Enzymes - genetics Female Genes Genomes HEK293 Cells HeLa Cells Humans Menopause, Premature - genetics Middle Aged Mutagenesis Mutant Chimeric Proteins - genetics Mutation Poly-ADP-Ribose Binding Proteins Primary Ovarian Insufficiency - genetics Proteins Recombinant Fusion Proteins - genetics RNA polymerase Sequence Analysis, DNA Studies |
| title | CSB-PGBD3 Mutations Cause Premature Ovarian Failure |
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