2. Academic Validation
  3. A loss-of-function NUAK2 mutation in humans causes anencephaly due to impaired Hippo-YAP signaling

A loss-of-function NUAK2 mutation in humans causes anencephaly due to impaired Hippo-YAP signaling

  • J Exp Med. 2020 Dec 7;217(12):e20191561. doi: 10.1084/jem.20191561.
Carine Bonnard 1,  Naveenan Navaratnam 2,  Kakaly Ghosh 1,  Puck Wee Chan 1,  Thong Teck Tan 1,  Oz Pomp 1,  Alvin Yu Jin Ng 3,  Sumanty Tohari 3,  Rishita Changede 4,  David Carling 2,  Byrappa Venkatesh 3 5,  Umut Altunoglu 6 7,  Hülya Kayserili 6 7,  Bruno Reversade 1 3 5 7
Affiliations

Affiliations

  • 1 Human Genetics and Embryology Laboratory, Institute of Medical Biology, Agency for Science, Technology and Research, Singapore.
  • 2 Medical Research Council London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London, UK.
  • 3 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore.
  • 4 Mechanobiology Institute, National University of Singapore, Singapore.
  • 5 Department of Paediatrics, National University of Singapore, Singapore.
  • 6 Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
  • 7 Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey.
PMID: 32845958 DOI: 10.1084/jem.20191561
Abstract

Failure of neural tube closure during embryonic development can result in anencephaly, one of the most common birth defects in humans. 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-amino 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-like 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.

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