論文

査読有り 国際誌
2018年4月15日

Loss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders.

Human molecular genetics
  • Takeshi Mizuguchi
  • Mitsuko Nakashima
  • Mitsuhiro Kato
  • Nobuhiko Okamoto
  • Hirokazu Kurahashi
  • Nina Ekhilevitch
  • Masaaki Shiina
  • Gen Nishimura
  • Takashi Shibata
  • Muneaki Matsuo
  • Tae Ikeda
  • Kazuhiro Ogata
  • Naomi Tsuchida
  • Satomi Mitsuhashi
  • Satoko Miyatake
  • Atsushi Takata
  • Noriko Miyake
  • Kenichiro Hata
  • Tadashi Kaname
  • Yoichi Matsubara
  • Hirotomo Saitsu
  • Naomichi Matsumoto
  • 全て表示

27
8
開始ページ
1421
終了ページ
1433
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1093/hmg/ddy052

Calcineurin is a calcium (Ca2+)/calmodulin-regulated protein phosphatase that mediates Ca2+-dependent signal transduction. Here, we report six heterozygous mutations in a gene encoding the alpha isoform of the calcineurin catalytic subunit (PPP3CA). Notably, mutations were observed in different functional domains: in addition to three catalytic domain mutations, two missense mutations were found in the auto-inhibitory (AI) domain. One additional frameshift insertion that caused premature termination was also identified. Detailed clinical evaluation of the six individuals revealed clinically unexpected consequences of the PPP3CA mutations. First, the catalytic domain mutations and frameshift mutation were consistently found in patients with nonsyndromic early onset epileptic encephalopathy. In contrast, the AI domain mutations were associated with multiple congenital abnormalities including craniofacial dysmorphism, arthrogryposis and short stature. In addition, one individual showed severe skeletal developmental defects, namely, severe craniosynostosis and gracile bones (severe bone slenderness and perinatal fractures). Using a yeast model system, we showed that the catalytic and AI domain mutations visibly result in decreased and increased calcineurin signaling, respectively. These findings indicate that different functional effects of PPP3CA mutations are associated with two distinct disorders and suggest that functional approaches using a simple cellular system provide a tool for resolving complex genotype-phenotype correlations.

リンク情報
DOI
https://doi.org/10.1093/hmg/ddy052
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/29432562
ID情報
  • DOI : 10.1093/hmg/ddy052
  • ISSN : 0964-6906
  • PubMed ID : 29432562

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