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The intelligence quotient (IQ) motif and SEC7 domain containing protein 2 gene (<jats:italic>IQSEC2<\/jats:italic>) is located on the X-chromosome and harbors mutations that contribute to non-syndromic ID with and without early-onset seizure phenotypes in both sexes. Although IQ and Sec7 domain mutations lead to partial loss of <jats:italic>IQSEC2<\/jats:italic> enzymatic activity, the <jats:italic>in vivo<\/jats:italic> pathogenesis resulting from these mutations is not known. Here we reveal that <jats:italic>IQSEC2<\/jats:italic> has a key role in dendritic spine morphology. Partial loss-of-function mutations were modeled using a lentiviral short hairpin RNA (shRNA) approach, which achieved a 57% knockdown of <jats:italic>Iqsec2<\/jats:italic> expression in primary hippocampal cell cultures from mice. Investigating gross morphological parameters after 8 days of <jats:italic>in vitro<\/jats:italic> culture (8DIV) identified a 32% reduction in primary axon length, in contrast to a 27% and 31% increase in the number and complexity of dendrites protruding from the cell body, respectively. This increase in dendritic complexity and spread was carried through dendritic spine development, with a 34% increase in the number of protrusions per dendritic segment compared with controls at 15DIV. Although the number of dendritic spines had normalized by 21DIV, a reduction was noted in the number of immature spines. In contrast, when modeling increased dosage, overexpression of wild-type <jats:italic>IQSEC2<\/jats:italic> led to neurons with shorter axons that were more compact and displayed simpler dendritic branching. Disturbances to dendritic morphology due to knockdown of <jats:italic>Iqsec2<\/jats:italic> were recapitulated in neurons from <jats:italic>Iqsec2<\/jats:italic> knockout mice generated in our laboratory using CRISPR\/Cas9 technology. These observations provide evidence of dosage sensitivity for <jats:italic>IQSEC2<\/jats:italic>, which normally escapes X-inactivation in females, and links these disturbances in expression to alterations in the morphology of developing neurons.<\/jats:p>","DOI":"10.1038\/tp.2017.81","type":"journal-article","created":{"date-parts":[[2017,5,2]],"date-time":"2017-05-02T13:42:04Z","timestamp":1493732524000},"page":"e1110-e1110","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Incorrect dosage of IQSEC2, a known intellectual disability and epilepsy gene, disrupts dendritic spine morphogenesis"],"prefix":"10.1038","volume":"7","author":[{"given":"S J","family":"Hinze","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M R","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Lie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Jolly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Field","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S C","family":"Barry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R J","family":"Harvey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0157-3084","authenticated-orcid":false,"given":"C","family":"Shoubridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,5,2]]},"reference":[{"key":"BFtp201781_CR1","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.neuint.2007.04.029","volume":"51","author":"Y Sekino","year":"2007","unstructured":"Sekino Y, Kojima N, Shirao T . 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