{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T13:56:58Z","timestamp":1787061418241,"version":"build-2736575974"},"reference-count":42,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,29]],"date-time":"2022-09-29T00:00:00Z","timestamp":1664409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT098051"],"award-info":[{"award-number":["WT098051"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["ANR-11-PDOC-0029"],"award-info":[{"award-number":["ANR-11-PDOC-0029"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["NR-18-CE12-0009-01"],"award-info":[{"award-number":["NR-18-CE12-0009-01"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"French National Research Agency","award":["WT098051"],"award-info":[{"award-number":["WT098051"]}]},{"name":"French National Research Agency","award":["ANR-11-PDOC-0029"],"award-info":[{"award-number":["ANR-11-PDOC-0029"]}]},{"name":"French National Research Agency","award":["NR-18-CE12-0009-01"],"award-info":[{"award-number":["NR-18-CE12-0009-01"]}]},{"name":"National Institute of Health and Medical Research","award":["WT098051"],"award-info":[{"award-number":["WT098051"]}]},{"name":"National Institute of Health and Medical Research","award":["ANR-11-PDOC-0029"],"award-info":[{"award-number":["ANR-11-PDOC-0029"]}]},{"name":"National Institute of Health and Medical Research","award":["NR-18-CE12-0009-01"],"award-info":[{"award-number":["NR-18-CE12-0009-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>CHARGE syndrome is a rare congenital disorder frequently caused by mutations in the chromodomain helicase DNA-binding protein-7 CHD7. Here, we developed and systematically characterized two genetic mouse models with identical, heterozygous loss-of-function mutation of the Chd7 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 Chd7 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 Chd7 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.<\/jats:p>","DOI":"10.3390\/ijms231911509","type":"journal-article","created":{"date-parts":[[2022,9,29]],"date-time":"2022-09-29T21:03:10Z","timestamp":1664485390000},"page":"11509","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Characterization of Two Mouse Chd7 Heterozygous Loss-of-Function Models Shows Dysgenesis of the Corpus Callosum and Previously Unreported Features of CHARGE Syndrome"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1533-3380","authenticated-orcid":false,"given":"Stephan C.","family":"Collins","sequence":"first","affiliation":[{"name":"Inserm UMR1231, University of Burgundy Franche-Comt\u00e9, 15 Boulevard Mar\u00e9chal de Lattre de Tassigny, 21070 Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie E.","family":"Vancollie","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute, Hinxton CB10 1SA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Mikhaleva","sequence":"additional","affiliation":[{"name":"Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christel","family":"Wagner","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Molecular and Cellular Biology, UMR7104, 67400 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Balz","sequence":"additional","affiliation":[{"name":"Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8087-4530","authenticated-orcid":false,"given":"Christopher J.","family":"Lelliott","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute, Hinxton CB10 1SA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1924-6807","authenticated-orcid":false,"given":"Binnaz","family":"Yalcin","sequence":"additional","affiliation":[{"name":"Inserm UMR1231, University of Burgundy Franche-Comt\u00e9, 15 Boulevard Mar\u00e9chal de Lattre de Tassigny, 21070 Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1038\/ng1407","article-title":"Mutations in a new member of the chromodomain gene family cause CHARGE syndrome","volume":"36","author":"Vissers","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1002\/ajmg.c.31591","article-title":"Phenotype and genotype analysis of a French cohort of 119 patients with CHARGE syndrome","volume":"175","author":"Legendre","year":"2017","journal-title":"Am. J. Med. Genet. Part C Semin. Med. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ghir.2017.12.011","article-title":"Hypothalamic abnormalities: Growth failure due to defects of the GHRH receptor","volume":"38","author":"Davalos","year":"2018","journal-title":"Growth Horm. IGF Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1002\/ajmg.c.31593","article-title":"Guidelines in CHARGE syndrome and the missing link: Cranial imaging","volume":"175","author":"Free","year":"2017","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e01305","DOI":"10.7554\/eLife.01305","article-title":"Deregulated FGF and homeotic gene expression underlies cerebellar vermis hypoplasia in CHARGE syndrome","volume":"2","author":"Yu","year":"2013","journal-title":"Elife"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1002\/ajmg.a.37435","article-title":"Atypical phenotypes associated with pathogenic CHD7 variants and a proposal for broadening CHARGE syndrome clinical diagnostic criteria","volume":"170A","author":"Hale","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1002\/ajmg.c.31592","article-title":"New insights and advances in CHARGE syndrome: Diagnosis, etiologies, treatments, and research discoveries","volume":"175","author":"Martin","year":"2017","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature10163","article-title":"A conditional knockout resource for the genome-wide study of mouse gene function","volume":"474","author":"Skarnes","year":"2011","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1093\/hmg\/ddt610","article-title":"CHD7 interacts with BMP R-SMADs to epigenetically regulate cardiogenesis in mice","volume":"23","author":"Liu","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"28847","DOI":"10.1073\/pnas.2005222117","article-title":"CHD7 regulates cardiovascular development through ATP-dependent and -independent activities","volume":"117","author":"Yan","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.ydbio.2015.06.017","article-title":"A critical role for the chromatin remodeller CHD7 in anterior mesoderm during cardiovascular development","volume":"405","author":"Payne","year":"2015","journal-title":"Dev. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"14758","DOI":"10.1038\/ncomms14758","article-title":"Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme","volume":"8","author":"Feng","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.stem.2013.05.002","article-title":"The Chromatin Remodeler CHD7 Regulates Adult Neurogenesis via Activation of SoxC Transcription Factors","volume":"13","author":"Feng","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1172\/JCI83408","article-title":"The chromatin remodeling factor CHD7 controls cerebellar development by regulating reelin expression","volume":"127","author":"Whittaker","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/stem.1822","article-title":"CHD7 Maintains Neural Stem Cell Quiescence and Prevents Premature Stem Cell Depletion in the Adult Hippocampus","volume":"33","author":"Jones","year":"2015","journal-title":"Stem Cells"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10290","DOI":"10.1523\/JNEUROSCI.1109-17.2017","article-title":"Chd7 Collaborates with Sox2 to Regulate Activation of Oligodendrocyte Precursor Cells after Spinal Cord Injury","volume":"37","author":"Doi","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3465","DOI":"10.1038\/s41467-019-11431-2","article-title":"Large-scale neuroanatomical study uncovers 198 gene associations in mouse brain morphogenesis","volume":"10","author":"Collins","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5702","DOI":"10.1038\/s41467-021-25846-3","article-title":"CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum","volume":"12","author":"Reddy","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ingham, N.J., Pearson, S.A., Vancollie, V.E., Rook, V., Lewis, M.A., Chen, J., Buniello, A., Martelletti, E., Preite, L., and Lam, C.C. (2019). Mouse screen reveals multiple new genes underlying mouse and human hearing loss. PLoS Biol., 17.","DOI":"10.1371\/journal.pbio.3000194"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1038\/s42003-021-02788-6","article-title":"The chromatin remodelling factor Chd7 protects auditory neurons and sensory hair cells from stress-induced degeneration","volume":"4","author":"Ahmed","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3463","DOI":"10.1093\/hmg\/ddi375","article-title":"Multiple mutations in mouse Chd7 provide models for CHARGE syndrome","volume":"14","author":"Bosman","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/ejhg.2009.158","article-title":"Study of smell and reproductive organs in a mouse model for CHARGE syndrome","volume":"18","author":"Bergman","year":"2010","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1007\/s00439-014-1444-2","article-title":"CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance","volume":"133","author":"Schulz","year":"2014","journal-title":"Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/s13041-016-0275-6","article-title":"CHD7 promotes proliferation of neural stem cells mediated by MIF","volume":"9","author":"Ohta","year":"2016","journal-title":"Mol. Brain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1002\/cpmo.12","article-title":"Histomorphological Phenotyping of the Adult Mouse Brain","volume":"6","author":"Mikhaleva","year":"2016","journal-title":"Curr. Protoc. Mouse Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.ajpath.2012.05.006","article-title":"The mutation in Chd7 causes misexpression of Bmp4 and developmental defects in telencephalic midline","volume":"181","author":"Jiang","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.neubiorev.2020.11.031","article-title":"Time to put the mammillothalamic pathway into context","volume":"121","author":"Dillingham","year":"2021","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"628424","DOI":"10.3389\/fnhum.2021.628424","article-title":"The Role of White Matter in the Neural Control of Swallowing: A Systematic Review","volume":"15","author":"Alvar","year":"2021","journal-title":"Front. Hum. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"760311","DOI":"10.3389\/fnsys.2021.760311","article-title":"Non-human Primate Models to Explore the Adaptive Mechanisms After Stroke","volume":"15","author":"Higo","year":"2021","journal-title":"Front. Syst. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1097\/WCO.0000000000000749","article-title":"Alternative routes for recovery of hand functions after corticospinal tract injury in primates and rodents","volume":"32","author":"Isa","year":"2019","journal-title":"Curr. Opin. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1002\/ajmg.a.30549","article-title":"CHARGE syndrome: Developmental and behavioral data","volume":"133A","author":"Souriau","year":"2005","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1002\/ajmg.a.30543","article-title":"Behavioral features of CHARGE syndrome (Hall-Hittner syndrome) comparison with Down syndrome, Prader-Willi syndrome, and Williams syndrome","volume":"133A","author":"Graham","year":"2005","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Yalcin, B., Nicod, J., Bhomra, A., Davidson, S., Cleak, J., Farinelli, L., \u00d8ster\u00e5s, M., Whitley, A., Yuan, W., and Gan, X. (2010). Commercially available outbred mice for genome-wide association studies. PLoS Genet., 6.","DOI":"10.1371\/journal.pgen.1001085"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/BF00254508","article-title":"Cephalic phase, reflex insulin secretion. Neuroanatomical and physiological characterization","volume":"20","author":"Berthoud","year":"1981","journal-title":"Diabetologia"},{"key":"ref_35","first-page":"R364","article-title":"Relationship between sympathetic activity and diet-induced obesity in two rat strains","volume":"245","author":"Levin","year":"1983","journal-title":"Am. J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"R82","DOI":"10.1186\/gb-2013-14-7-r82","article-title":"A comparative phenotypic and genomic analysis of C57BL\/6J and C57BL\/6N mouse strains","volume":"14","author":"Simon","year":"2013","journal-title":"Genome Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.ejmg.2018.01.008","article-title":"A case of CHARGE syndrome associated with hyperinsulinemic hypoglycemia in infancy","volume":"61","author":"Sekiguchi","year":"2018","journal-title":"Eur. J. Med. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1038\/s41431-019-0465-7","article-title":"A functional assay to study the pathogenicity of CHD7 protein variants encountered in CHARGE syndrome patients","volume":"27","author":"Brajadenta","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.2337\/db15-1489","article-title":"Increased Expression of the Diabetes Gene SOX4 Reduces Insulin Secretion by Impaired Fusion Pore Expansion","volume":"65","author":"Collins","year":"2016","journal-title":"Diabetes"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1002\/ajmg.c.31594","article-title":"Immunodeficiency in CHARGE syndrome","volume":"175","author":"Mehr","year":"2017","journal-title":"Am. J. Med. Genet. Part C Semin. Med. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.3174\/ajnr.A5297","article-title":"Head and Neck MRI Findings in CHARGE Syndrome","volume":"38","author":"Hoch","year":"2017","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.cell.2013.06.022","article-title":"Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes","volume":"154","author":"White","year":"2013","journal-title":"Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/11509\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:41:53Z","timestamp":1760143313000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/11509"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,29]]},"references-count":42,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms231911509"],"URL":"https:\/\/doi.org\/10.3390\/ijms231911509","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,29]]}}}