Friedreich's Ataxia Induced Pluripotent Stem Cells Model Intergenerational GAA⋅TTC Triplet Repeat Instability
The inherited neurodegenerative disease Friedreich's ataxia (FRDA) is caused by GAA⋅TTC triplet repeat hyperexpansions within the first intron of the FXN gene, encoding the mitochondrial protein frataxin. Long GAA⋅TTC repeats cause heterochromatin-mediated gene silencing and loss of frataxin in...
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| Veröffentlicht in: | Cell stem cell 2010-11, Vol.7 (5), p.631-637 |
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| creator | Ku, Sherman Soragni, Elisabetta Campau, Erica Thomas, Elizabeth A. Altun, Gulsah Laurent, Louise C. Loring, Jeanne F. Napierala, Marek Gottesfeld, Joel M. |
| description | The inherited neurodegenerative disease Friedreich's ataxia (FRDA) is caused by GAA⋅TTC triplet repeat hyperexpansions within the first intron of the
FXN gene, encoding the mitochondrial protein frataxin. Long GAA⋅TTC repeats cause heterochromatin-mediated gene silencing and loss of frataxin in affected individuals. We report the derivation of induced pluripotent stem cells (iPSCs) from FRDA patient fibroblasts by transcription factor reprogramming.
FXN gene repression is maintained in the iPSCs, as are the global gene expression signatures reflecting the human disease. GAA⋅TTC repeats uniquely in
FXN in the iPSCs exhibit repeat instability similar to patient families, where they expand and/or contract with discrete changes in length between generations. The mismatch repair enzyme MSH2, implicated in repeat instability in other triplet repeat diseases, is highly expressed in pluripotent cells and occupies
FXN intron 1, and shRNA silencing of
MSH2 impedes repeat expansion, providing a possible molecular explanation for repeat expansion in FRDA.
► FRDA iPSCs retain key molecular features characteristic of the human disease ► GAA•TTC repeat instability is observed in iPSCs in the disease-relevant
FXN gene ► Repeat instability is dependent on the mismatch repair enzyme MSH2 |
| doi_str_mv | 10.1016/j.stem.2010.09.014 |
| format | Article |
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FXN gene, encoding the mitochondrial protein frataxin. Long GAA⋅TTC repeats cause heterochromatin-mediated gene silencing and loss of frataxin in affected individuals. We report the derivation of induced pluripotent stem cells (iPSCs) from FRDA patient fibroblasts by transcription factor reprogramming.
FXN gene repression is maintained in the iPSCs, as are the global gene expression signatures reflecting the human disease. GAA⋅TTC repeats uniquely in
FXN in the iPSCs exhibit repeat instability similar to patient families, where they expand and/or contract with discrete changes in length between generations. The mismatch repair enzyme MSH2, implicated in repeat instability in other triplet repeat diseases, is highly expressed in pluripotent cells and occupies
FXN intron 1, and shRNA silencing of
MSH2 impedes repeat expansion, providing a possible molecular explanation for repeat expansion in FRDA.
► FRDA iPSCs retain key molecular features characteristic of the human disease ► GAA•TTC repeat instability is observed in iPSCs in the disease-relevant
FXN gene ► Repeat instability is dependent on the mismatch repair enzyme MSH2</description><identifier>ISSN: 1934-5909</identifier><identifier>EISSN: 1875-9777</identifier><identifier>DOI: 10.1016/j.stem.2010.09.014</identifier><identifier>PMID: 21040903</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Cells, Cultured ; DNA Repeat Expansion ; Frataxin ; Friedreich Ataxia - genetics ; Humans ; Induced Pluripotent Stem Cells ; Iron-Binding Proteins - genetics ; Microsatellite Instability ; Trinucleotide Repeat Expansion - genetics</subject><ispartof>Cell stem cell, 2010-11, Vol.7 (5), p.631-637</ispartof><rights>2010 Elsevier Inc.</rights><rights>Copyright © 2010 Elsevier Inc. All rights reserved.</rights><rights>2010 ll Press. All rights reserved. 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3974-7a637f44c134db418fcd361ed417dd99b29ccf4b90a97ff0f8342e713528a3413</citedby><cites>FETCH-LOGICAL-c3974-7a637f44c134db418fcd361ed417dd99b29ccf4b90a97ff0f8342e713528a3413</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.stem.2010.09.014$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,777,781,882,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21040903$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ku, Sherman</creatorcontrib><creatorcontrib>Soragni, Elisabetta</creatorcontrib><creatorcontrib>Campau, Erica</creatorcontrib><creatorcontrib>Thomas, Elizabeth A.</creatorcontrib><creatorcontrib>Altun, Gulsah</creatorcontrib><creatorcontrib>Laurent, Louise C.</creatorcontrib><creatorcontrib>Loring, Jeanne F.</creatorcontrib><creatorcontrib>Napierala, Marek</creatorcontrib><creatorcontrib>Gottesfeld, Joel M.</creatorcontrib><title>Friedreich's Ataxia Induced Pluripotent Stem Cells Model Intergenerational GAA⋅TTC Triplet Repeat Instability</title><title>Cell stem cell</title><addtitle>Cell Stem Cell</addtitle><description>The inherited neurodegenerative disease Friedreich's ataxia (FRDA) is caused by GAA⋅TTC triplet repeat hyperexpansions within the first intron of the
FXN gene, encoding the mitochondrial protein frataxin. Long GAA⋅TTC repeats cause heterochromatin-mediated gene silencing and loss of frataxin in affected individuals. We report the derivation of induced pluripotent stem cells (iPSCs) from FRDA patient fibroblasts by transcription factor reprogramming.
FXN gene repression is maintained in the iPSCs, as are the global gene expression signatures reflecting the human disease. GAA⋅TTC repeats uniquely in
FXN in the iPSCs exhibit repeat instability similar to patient families, where they expand and/or contract with discrete changes in length between generations. The mismatch repair enzyme MSH2, implicated in repeat instability in other triplet repeat diseases, is highly expressed in pluripotent cells and occupies
FXN intron 1, and shRNA silencing of
MSH2 impedes repeat expansion, providing a possible molecular explanation for repeat expansion in FRDA.
► FRDA iPSCs retain key molecular features characteristic of the human disease ► GAA•TTC repeat instability is observed in iPSCs in the disease-relevant
FXN gene ► Repeat instability is dependent on the mismatch repair enzyme MSH2</description><subject>Cells, Cultured</subject><subject>DNA Repeat Expansion</subject><subject>Frataxin</subject><subject>Friedreich Ataxia - genetics</subject><subject>Humans</subject><subject>Induced Pluripotent Stem Cells</subject><subject>Iron-Binding Proteins - genetics</subject><subject>Microsatellite Instability</subject><subject>Trinucleotide Repeat Expansion - genetics</subject><issn>1934-5909</issn><issn>1875-9777</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kd9OHCEUh4lp47_2BXrRcOfVrDAwy5AYk82mWhObGru9JgycUTbssAXG1Afwyrf0Scpm1ehNryDwnd_h8CH0hZIJJXR6vJykDKtJTcoBkRNC-Q7ap61oKimE-FD2kvGqkUTuoYOUloQ0ghKxi_ZqSjiRhO2jcBYd2AjO3B4lPMv6r9P4YrCjAYuv_BjdOmQYMv5VWuE5eJ_wj2DBFyhDvIEBos4uDNrj89ns6fFhsZjjRSnzkPE1rEHngqasO-ddvv-EPvbaJ_j8vB6i32ffFvPv1eXP84v57LIyTApeCT1loufcUMZtx2nbG8umFCynwlopu1oa0_NOEi1F35O-ZbwGQVlTt5pxyg7R6TZ3PXYrsKaMELVX6-hWOt6roJ16fzO4W3UT7lQtWzFlTQk4eg6I4c8IKauVS6bMrwcIY1Ky4Y0UlNaFrLekiSGlCP1rF0rURpRaqo0otRGliFRFVCn6-vZ9ryUvZgpwsgWg_NKdg6iScTAULS6CycoG97_8f0c3p1g</recordid><startdate>20101105</startdate><enddate>20101105</enddate><creator>Ku, Sherman</creator><creator>Soragni, Elisabetta</creator><creator>Campau, Erica</creator><creator>Thomas, Elizabeth A.</creator><creator>Altun, Gulsah</creator><creator>Laurent, Louise C.</creator><creator>Loring, Jeanne F.</creator><creator>Napierala, Marek</creator><creator>Gottesfeld, Joel M.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>7QO</scope><scope>7T5</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20101105</creationdate><title>Friedreich's Ataxia Induced Pluripotent Stem Cells Model Intergenerational GAA⋅TTC Triplet Repeat Instability</title><author>Ku, Sherman ; Soragni, Elisabetta ; Campau, Erica ; Thomas, Elizabeth A. ; Altun, Gulsah ; Laurent, Louise C. ; Loring, Jeanne F. ; Napierala, Marek ; Gottesfeld, Joel M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3974-7a637f44c134db418fcd361ed417dd99b29ccf4b90a97ff0f8342e713528a3413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Cells, Cultured</topic><topic>DNA Repeat Expansion</topic><topic>Frataxin</topic><topic>Friedreich Ataxia - genetics</topic><topic>Humans</topic><topic>Induced Pluripotent Stem Cells</topic><topic>Iron-Binding Proteins - genetics</topic><topic>Microsatellite Instability</topic><topic>Trinucleotide Repeat Expansion - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ku, Sherman</creatorcontrib><creatorcontrib>Soragni, Elisabetta</creatorcontrib><creatorcontrib>Campau, Erica</creatorcontrib><creatorcontrib>Thomas, Elizabeth A.</creatorcontrib><creatorcontrib>Altun, Gulsah</creatorcontrib><creatorcontrib>Laurent, Louise C.</creatorcontrib><creatorcontrib>Loring, Jeanne F.</creatorcontrib><creatorcontrib>Napierala, Marek</creatorcontrib><creatorcontrib>Gottesfeld, Joel M.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell stem cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ku, Sherman</au><au>Soragni, Elisabetta</au><au>Campau, Erica</au><au>Thomas, Elizabeth A.</au><au>Altun, Gulsah</au><au>Laurent, Louise C.</au><au>Loring, Jeanne F.</au><au>Napierala, Marek</au><au>Gottesfeld, Joel M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Friedreich's Ataxia Induced Pluripotent Stem Cells Model Intergenerational GAA⋅TTC Triplet Repeat Instability</atitle><jtitle>Cell stem cell</jtitle><addtitle>Cell Stem Cell</addtitle><date>2010-11-05</date><risdate>2010</risdate><volume>7</volume><issue>5</issue><spage>631</spage><epage>637</epage><pages>631-637</pages><issn>1934-5909</issn><eissn>1875-9777</eissn><abstract>The inherited neurodegenerative disease Friedreich's ataxia (FRDA) is caused by GAA⋅TTC triplet repeat hyperexpansions within the first intron of the
FXN gene, encoding the mitochondrial protein frataxin. Long GAA⋅TTC repeats cause heterochromatin-mediated gene silencing and loss of frataxin in affected individuals. We report the derivation of induced pluripotent stem cells (iPSCs) from FRDA patient fibroblasts by transcription factor reprogramming.
FXN gene repression is maintained in the iPSCs, as are the global gene expression signatures reflecting the human disease. GAA⋅TTC repeats uniquely in
FXN in the iPSCs exhibit repeat instability similar to patient families, where they expand and/or contract with discrete changes in length between generations. The mismatch repair enzyme MSH2, implicated in repeat instability in other triplet repeat diseases, is highly expressed in pluripotent cells and occupies
FXN intron 1, and shRNA silencing of
MSH2 impedes repeat expansion, providing a possible molecular explanation for repeat expansion in FRDA.
► FRDA iPSCs retain key molecular features characteristic of the human disease ► GAA•TTC repeat instability is observed in iPSCs in the disease-relevant
FXN gene ► Repeat instability is dependent on the mismatch repair enzyme MSH2</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>21040903</pmid><doi>10.1016/j.stem.2010.09.014</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Cells, Cultured DNA Repeat Expansion Frataxin Friedreich Ataxia - genetics Humans Induced Pluripotent Stem Cells Iron-Binding Proteins - genetics Microsatellite Instability Trinucleotide Repeat Expansion - genetics |
| title | Friedreich's Ataxia Induced Pluripotent Stem Cells Model Intergenerational GAA⋅TTC Triplet Repeat Instability |
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