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The prevalence of ID and ASD is higher in males compared to females, with unknown mechanisms. Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type (MRXSCJ), is caused by loss-of-function mutations of lysine demethylase 5C (KDM5C), a histone H3K4 demethylase gene. KDM5C escapes X-inactivation, thereby presenting at a higher level in females. Initially, MRXSCJ was exclusively reported in males, while it is increasingly evident that females with heterozygous KDM5C mutations can show cognitive deficits. The mouse model of MRXSCJ, male Kdm5c-hemizygous knockout animals, recapitulates key features of human male patients. However, the behavioral and molecular traits of Kdm5c-heterozygous female mice remain incompletely characterized. Here, we report that gene expression and behavioral abnormalities are readily detectable in Kdm5c-heterozygous female mice, demonstrating the requirement for a higher KDM5C dose in females. Furthermore, we found both shared and sex-specific consequences of a reduced KDM5C dose in social behavior, gene expression, and genetic interaction with the counteracting enzyme KMT2A. These observations provide an essential insight into the sex-biased manifestation of neurodevelopmental disorders and sex chromosome evolution.<\/jats:p>","DOI":"10.3390\/cells12040637","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T02:52:56Z","timestamp":1676515976000},"page":"637","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Sexually Dimorphic Alterations in the Transcriptome and Behavior with Loss of Histone Demethylase KDM5C"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1845-9050","authenticated-orcid":false,"given":"Katherine M.","family":"Bonefas","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina N.","family":"Vallianatos","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Genetics and Genomics Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brynne","family":"Raines","sequence":"additional","affiliation":[{"name":"Department of Psychology, College of LS&A, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5676-1579","authenticated-orcid":false,"given":"Natalie C.","family":"Tronson","sequence":"additional","affiliation":[{"name":"Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Psychology, College of LS&A, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2280-7422","authenticated-orcid":false,"given":"Shigeki","family":"Iwase","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Genetics and Genomics Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/nature13772","article-title":"Synaptic, transcriptional and chromatin genes disrupted in autism","volume":"515","author":"He","year":"2014","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.ajhg.2017.11.013","article-title":"Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders","volume":"102","author":"Faundes","year":"2017","journal-title":"Am. 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