Characterization of Two Mouse <i>Chd7</i> Heterozygous Loss-of-Function Models Shows Dysgenesis of the Corpus Callosum and Previously Unreported Features of CHARGE Syndrome
CHARGE syndrome is a rare congenital disorder frequently caused by mutations in the chromodomain helicase DNA-binding protein-7 <i>CHD7</i>. Here, we developed and systematically characterized two genetic mouse models with identical, heterozygous loss-of-function mutation of the <i>...
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| Format: | Article |
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MDPI AG
2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/19/11509 |
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| author | Stephan C. Collins Valerie E. Vancollie Anna Mikhaleva Christel Wagner Rebecca Balz Christopher J. Lelliott Binnaz Yalcin |
| author_facet | Stephan C. Collins Valerie E. Vancollie Anna Mikhaleva Christel Wagner Rebecca Balz Christopher J. Lelliott Binnaz Yalcin |
| author_sort | Stephan C. Collins |
| collection | DOAJ |
| description | CHARGE syndrome is a rare congenital disorder frequently caused by mutations in the chromodomain helicase DNA-binding protein-7 <i>CHD7</i>. Here, we developed and systematically characterized two genetic mouse models with identical, heterozygous loss-of-function mutation of the <i>Chd7</i> gene engineered on inbred and outbred genetic backgrounds. We found that both models showed consistent phenotypes with the core clinical manifestations seen in CHARGE syndrome, but the phenotypes in the inbred <i>Chd7</i> model were more severe, sometimes having reduced penetrance and included dysgenesis of the corpus callosum, hypoplasia of the hippocampus, abnormal retrosplenial granular cortex, ventriculomegaly, hyperactivity, growth delays, impaired grip strength and repetitive behaviors. Interestingly, we also identified previously unreported features including reduced levels of basal insulin and reduced blood lipids. We suggest that the phenotypic variation reported in individuals diagnosed with CHARGE syndrome is likely due to the genetic background and modifiers. Finally, our study provides a valuable resource, making it possible for mouse biologists interested in <i>Chd7</i> to make informed choices on which mouse model they should use to study phenotypes of interest and investigate in more depth the underlying cellular and molecular mechanisms. |
| first_indexed | 2024-03-09T21:40:32Z |
| format | Article |
| id | doaj.art-be82312055b24513adaf4c26906aeec8 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:40:32Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-be82312055b24513adaf4c26906aeec82023-11-23T20:34:23ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123191150910.3390/ijms231911509Characterization of Two Mouse <i>Chd7</i> Heterozygous Loss-of-Function Models Shows Dysgenesis of the Corpus Callosum and Previously Unreported Features of CHARGE SyndromeStephan C. Collins0Valerie E. Vancollie1Anna Mikhaleva2Christel Wagner3Rebecca Balz4Christopher J. Lelliott5Binnaz Yalcin6Inserm UMR1231, University of Burgundy Franche-Comté, 15 Boulevard Maréchal de Lattre de Tassigny, 21070 Dijon, FranceWellcome Sanger Institute, Hinxton CB10 1SA, UKCenter for Integrative Genomics, University of Lausanne, 1015 Lausanne, SwitzerlandInstitute of Genetics and Molecular and Cellular Biology, UMR7104, 67400 Illkirch, FranceCenter for Integrative Genomics, University of Lausanne, 1015 Lausanne, SwitzerlandWellcome Sanger Institute, Hinxton CB10 1SA, UKInserm UMR1231, University of Burgundy Franche-Comté, 15 Boulevard Maréchal de Lattre de Tassigny, 21070 Dijon, FranceCHARGE syndrome is a rare congenital disorder frequently caused by mutations in the chromodomain helicase DNA-binding protein-7 <i>CHD7</i>. Here, we developed and systematically characterized two genetic mouse models with identical, heterozygous loss-of-function mutation of the <i>Chd7</i> gene engineered on inbred and outbred genetic backgrounds. We found that both models showed consistent phenotypes with the core clinical manifestations seen in CHARGE syndrome, but the phenotypes in the inbred <i>Chd7</i> model were more severe, sometimes having reduced penetrance and included dysgenesis of the corpus callosum, hypoplasia of the hippocampus, abnormal retrosplenial granular cortex, ventriculomegaly, hyperactivity, growth delays, impaired grip strength and repetitive behaviors. Interestingly, we also identified previously unreported features including reduced levels of basal insulin and reduced blood lipids. We suggest that the phenotypic variation reported in individuals diagnosed with CHARGE syndrome is likely due to the genetic background and modifiers. Finally, our study provides a valuable resource, making it possible for mouse biologists interested in <i>Chd7</i> to make informed choices on which mouse model they should use to study phenotypes of interest and investigate in more depth the underlying cellular and molecular mechanisms.https://www.mdpi.com/1422-0067/23/19/11509neurodevelopmental disordersCHARGE syndromedysgenesis of the corpus callosummouse modelsCHD7 |
| spellingShingle | Stephan C. Collins Valerie E. Vancollie Anna Mikhaleva Christel Wagner Rebecca Balz Christopher J. Lelliott Binnaz Yalcin Characterization of Two Mouse <i>Chd7</i> Heterozygous Loss-of-Function Models Shows Dysgenesis of the Corpus Callosum and Previously Unreported Features of CHARGE Syndrome International Journal of Molecular Sciences neurodevelopmental disorders CHARGE syndrome dysgenesis of the corpus callosum mouse models CHD7 |
| title | Characterization of Two Mouse <i>Chd7</i> Heterozygous Loss-of-Function Models Shows Dysgenesis of the Corpus Callosum and Previously Unreported Features of CHARGE Syndrome |
| title_full | Characterization of Two Mouse <i>Chd7</i> Heterozygous Loss-of-Function Models Shows Dysgenesis of the Corpus Callosum and Previously Unreported Features of CHARGE Syndrome |
| title_fullStr | Characterization of Two Mouse <i>Chd7</i> Heterozygous Loss-of-Function Models Shows Dysgenesis of the Corpus Callosum and Previously Unreported Features of CHARGE Syndrome |
| title_full_unstemmed | Characterization of Two Mouse <i>Chd7</i> Heterozygous Loss-of-Function Models Shows Dysgenesis of the Corpus Callosum and Previously Unreported Features of CHARGE Syndrome |
| title_short | Characterization of Two Mouse <i>Chd7</i> Heterozygous Loss-of-Function Models Shows Dysgenesis of the Corpus Callosum and Previously Unreported Features of CHARGE Syndrome |
| title_sort | characterization of two mouse i chd7 i heterozygous loss of function models shows dysgenesis of the corpus callosum and previously unreported features of charge syndrome |
| topic | neurodevelopmental disorders CHARGE syndrome dysgenesis of the corpus callosum mouse models CHD7 |
| url | https://www.mdpi.com/1422-0067/23/19/11509 |
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