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Most pathogenic mutations are located in the N-terminal region of the gene, which encodes a BRCT domain, suggesting an important function of this domain in brain size determination. To investigate the specific function of the N-terminal BRCT domain in vivo, we generated a mouse model lacking the N\u2019-BRCT domain of MCPH1 (referred as <jats:italic>Mcph1<\/jats:italic>-\u0394BR1). These mutant mice are viable, but exhibit reduced brain size, with a thinner cortex due to a reduction of neuroprogenitor populations and premature neurogenic differentiation. <jats:italic>Mcph1<\/jats:italic>-\u0394BR1 mice (both male and female) are infertile; however, almost all female mutants develop ovary tumours. <jats:italic>Mcph1<\/jats:italic>-\u0394BR1 MEF cells exhibit a defect in DNA damage response and DNA repair, and show the premature chromosome condensation (PCC) phenotype, a hallmark of MCPH1 patient cells and also Mcph1 knockout cells. In comparison with <jats:italic>Mcph1<\/jats:italic> complete knockout mice, <jats:italic>Mcph1<\/jats:italic>-\u0394BR1 mice faithfully reproduce all phenotypes, indicating an essential role of the N-terminal BRCT domain for the physiological function of MCPH1 in the control of brain size and gonad development as well as in multiple cellular processes.<\/jats:p>","DOI":"10.1038\/s41419-021-03406-3","type":"journal-article","created":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T10:05:38Z","timestamp":1612433138000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["The N-terminal BRCT domain determines MCPH1 function in brain development and fertility"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1022-9215","authenticated-orcid":false,"given":"Xiaoqian","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6544-1347","authenticated-orcid":false,"given":"Nadine","family":"Schneble-L\u00f6hnert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Kristofova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobing","family":"Qing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7007-3270","authenticated-orcid":false,"given":"Jan","family":"Labisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1348-6321","authenticated-orcid":false,"given":"Susanne","family":"Hofmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8974-4000","authenticated-orcid":false,"given":"Sandra","family":"Ehrenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9634-004X","authenticated-orcid":false,"given":"Mara","family":"Sannai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tjard","family":"J\u00f6r\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Ori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maren","family":"Godmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8336-3485","authenticated-orcid":false,"given":"Zhao-Qi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,1]]},"reference":[{"key":"3406_CR1","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1086\/341283","volume":"71","author":"AP Jackson","year":"2002","unstructured":"Jackson, A. 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