論文

査読有り 本文へのリンクあり
2020年12月1日

Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants

Scientific Reports
  • Tomoko Uehara
  • ,
  • Kota Abe
  • ,
  • Masayuki Oginuma
  • ,
  • Shizuka Ishitani
  • ,
  • Hiroshi Yoshihashi
  • ,
  • Nobuhiko Okamoto
  • ,
  • Toshiki Takenouchi
  • ,
  • Kenjiro Kosaki
  • ,
  • Tohru Ishitani

10
1
開始ページ
17575
終了ページ
17575
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/s41598-020-74642-4

Cyclin-dependent kinase 8 (CDK8) is a member of the CDK/Cyclin module of the mediator complex. A recent study reported that heterozygous missense CDK8 mutations cause a neurodevelopmental disorder in humans. The mechanistic basis of CDK8-related disorder has yet to be delineated. Here, we report 2 patients with de novo missense mutations within the kinase domain of CDK8 along with the results of in vitro and in vivo functional analyses using a zebrafish model. Patient 1 and Patient 2 had intellectual disabilities and congenital anomalies. Exome analyses showed that patient 1 had a heterozygous de novo missense p.G28A variant in the CDK8 (NM_001260.3) gene and patient 2 had a heterozygous de novo missense p.N156S variant in the CDK8 gene. We assessed the pathogenicity of these two variants using cultured-cells and zebrafish model. An in vitro kinase assay of human CDK8 showed that enzymes with a p.G28A or p.N156S substitution showed decreased kinase activity. An in vivo assays of zebrafish overexpression analyses also showed that the p.G28A and p.N156S alleles were hypomorphic alleles. Importantly, the inhibition of CDK8 kinase activity in zebrafish embryos using a specific chemical inhibitor induced craniofacial and heart defects similar to the patients’ phenotype. Taken together, zebrafish studies showed that non-synonymous variants in the kinase domain of CDK8 act as hypomorphic alleles causing human congenital disorder.

リンク情報
DOI
https://doi.org/10.1038/s41598-020-74642-4
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/33067521
Scopus
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85092552086&origin=inward 本文へのリンクあり
Scopus Citedby
https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=85092552086&origin=inward
ID情報
  • DOI : 10.1038/s41598-020-74642-4
  • eISSN : 2045-2322
  • PubMed ID : 33067521
  • SCOPUS ID : 85092552086

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