{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:13:34Z","timestamp":1768569214912,"version":"3.49.0"},"posted":{"date-parts":[[2025,1,17]]},"group-title":"Genetic and Genomic Medicine","reference-count":74,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T00:00:00Z","timestamp":1737072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Microcephaly affects 1 in 2,500 babies per year. Primary microcephaly results from aberrant neurogenesis leading to a small brain at birth. This is due to altered patterns of proliferation and\/or early differentiation of neurons. Premature differentiation of neurons is associated with defects in the centrosome and\/or primary cilia. In this study, we report on the first patients identified with\n                  <jats:italic>NUBP2<\/jats:italic>\n                  -deficiency and utilize a conditional mouse model to ascertain the molecular mechanisms associated with\n                  <jats:italic>NUBP2<\/jats:italic>\n                  -deficient primary microcephaly. We identified homozygous\n                  <jats:italic>NUBP2<\/jats:italic>\n                  variants in these patients who displayed profound primary microcephaly in addition to intrauterine growth restriction, cervical kyphosis, severe contractures of joints, and facial dysmorphia. We then generated a mouse model using\n                  <jats:italic>Emx1-Cre<\/jats:italic>\n                  to ablate\n                  <jats:italic>Nubp2<\/jats:italic>\n                  from the forebrain. The mice presented with severe microcephaly starting at E18.5. Neurospheres generated from the forebrain of\n                  <jats:italic>\n                    Emx1-Cre; Nubp2\n                    <jats:sup>flox\/flox<\/jats:sup>\n                  <\/jats:italic>\n                  conditional deletion mice were used to support the pathogenicity of the patient variants. We show that loss of\n                  <jats:italic>Nubp2<\/jats:italic>\n                  increases both canonical and non-canonical cell death, but that loss of\n                  <jats:italic>p53<\/jats:italic>\n                  fails to rescue microcephaly in the mouse model. Examination of neurogenesis in\n                  <jats:italic>\n                    Emx1-Cre; Nubp2\n                    <jats:sup>flox\/flox<\/jats:sup>\n                  <\/jats:italic>\n                  mice revealed distinct alterations in proliferation and cellular migration accompanied by supernumerary centrosomes and cilia. We therefore propose that\n                  <jats:italic>NUBP2<\/jats:italic>\n                  is a novel primary microcephaly-related gene and that the role of\n                  <jats:italic>Nubp2<\/jats:italic>\n                  in centrosome and cilia regulation is crucial for proper neurogenesis.\n                <\/jats:p>","DOI":"10.1101\/2025.01.16.25320041","type":"posted-content","created":{"date-parts":[[2025,1,18]],"date-time":"2025-01-18T00:00:14Z","timestamp":1737158414000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>NUBP2<\/i>\n                  deficiency disrupts the centrosome-check point in the brain and causes primary microcephaly"],"prefix":"10.64898","author":[{"given":"Rebekah","family":"Rushforth","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanan 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L","family":"Sawyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5886-873X","authenticated-orcid":false,"given":"Matthew","family":"Osmond","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wesam","family":"Kurdi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Firdous","family":"Abdulwahab","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"DiStasio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Care4Rare Canada Consortium","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kym 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