A homozygous loss-of-function camk2a mutation causes growth delay, frequent seizures and severe intellectual disability

Poh Hui Chia, Franklin Lei Zhong, Shinsuke Niwa, Carine Bonnard, Kagistia Hana Utami, Ruizhu Zeng, Hane Lee, Ascia Eskin, Stanley F. Nelson, William H. Xie, Samah Al-Tawalbeh, Mohammad El-Khateeb, Mohammad Shboul, Mahmoud A. Pouladi, Mohammed Al-Raqad, Bruno Reversade

研究成果: Article査読

35 被引用数 (Scopus)

抄録

Calcium/calmodulin-dependent protein kinase II (CAMK2) plays fundamental roles in synaptic plasticity that underlies learning and memory. Here, we describe a new recessive neurodevelopmental syndrome with global developmental delay, seizures and intellectual disability. Using linkage analysis and exome sequencing, we found that this disease maps to chromosome 5q31.1-q34 and is caused by a biallelic germline mutation in CAMK2A. The missense mutation, p. His477Tyr is located in the CAMK2A association domain that is critical for its function and localization. Biochemically, the p.His477Tyr mutant is defective in self-oligomerization and unable to assemble into the multimeric holoenzyme.In vivo, CAMK2A H477Y failed to rescue neuronal defects in C. elegans lacking unc-43, the ortholog of human CAMK2A. In vitro, neurons derived from patient iPSCs displayed profound synaptic defects. Together, our data demonstrate that a recessive germline mutation in CAMK2A leads to neurodevelopmental defects in humans and suggest that dysfunctional CAMK2 paralogs may contribute to other neurological disorders.

本文言語English
論文番号e32451
ジャーナルeLife
7
DOI
出版ステータスPublished - 2018 5月 22

ASJC Scopus subject areas

  • 神経科学(全般)
  • 生化学、遺伝学、分子生物学(全般)
  • 免疫学および微生物学(全般)

フィンガープリント

「A homozygous loss-of-function camk2a mutation causes growth delay, frequent seizures and severe intellectual disability」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル