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A family with recurrent anencephalic fetuses was investigated to understand its etiology and pathogenesis. Exome sequencing revealed a recessive germline 21-bp in-frame deletion in NUAK2 segregating with the disease. In vitro kinase assays demonstrated that the 7\u2013amino acid truncation in NUAK2, a serine\/threonine kinase, completely abrogated its catalytic activity. Patient-derived disease models including neural progenitor cells and cerebral organoids showed that loss of NUAK2 activity led to decreased Hippo signaling via cytoplasmic YAP retention. In neural tube\u2013like structures, endogenous NUAK2 colocalized apically with the actomyosin network, which was disrupted in patient cells, causing impaired nucleokinesis and apical constriction. Our results establish NUAK2 as an indispensable kinase for brain development in humans and suggest that a NUAK2-Hippo signaling axis regulates cytoskeletal processes that govern cell shape during neural tube closure.<\/jats:p>","DOI":"10.1084\/jem.20191561","type":"journal-article","created":{"date-parts":[[2020,8,25]],"date-time":"2020-08-25T13:42:00Z","timestamp":1598362920000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":58,"title":["A loss-of-function NUAK2 mutation in humans causes anencephaly due to impaired Hippo-YAP signaling"],"prefix":"10.1084","volume":"217","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1922-017X","authenticated-orcid":true,"given":"Carine","family":"Bonnard","sequence":"first","affiliation":[{"name":"Human Genetics and Embryology Laboratory, Institute of Medical Biology, Agency for Science, Technology and Research, Singapore 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