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

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 MatsubaraHirotomo Saitsu, Naomichi Matsumoto

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Calcineurin is a calcium (Ca 2+ )/calmodulin-regulated protein phosphatase that mediates Ca 2+ -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.

Original languageEnglish
Pages (from-to)1421-1433
Number of pages13
JournalHuman Molecular Genetics
Volume27
Issue number8
DOIs
Publication statusPublished - Apr 15 2018

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Mutation
Calcineurin
Catalytic Domain
Arthrogryposis
Multiple Abnormalities
Craniosynostoses
Frameshift Mutation
Phosphoprotein Phosphatases
Genetic Association Studies
Brain Diseases
Missense Mutation
Calmodulin
Signal Transduction
Protein Isoforms
Yeasts
Calcium
Bone and Bones
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Mizuguchi, T., Nakashima, M., Kato, M., Okamoto, N., Kurahashi, H., Ekhilevitch, N., ... Matsumoto, N. (2018). Loss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders. Human Molecular Genetics, 27(8), 1421-1433. https://doi.org/10.1093/hmg/ddy052

Loss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders. / Mizuguchi, Takeshi; Nakashima, Mitsuko; Kato, Mitsuhiro; Okamoto, Nobuhiko; Kurahashi, Hirokazu; Ekhilevitch, Nina; Shiina, Masaaki; Nishimura, Gen; Shibata, Takashi; Matsuo, Muneaki; Ikeda, Tae; Ogata, Kazuhiro; Tsuchida, Naomi; Mitsuhashi, Satomi; Miyatake, Satoko; Takata, Atsushi; Miyake, Noriko; Hata, Kenichiro; Kaname, Tadashi; Matsubara, Yoichi; Saitsu, Hirotomo; Matsumoto, Naomichi.

In: Human Molecular Genetics, Vol. 27, No. 8, 15.04.2018, p. 1421-1433.

Research output: Contribution to journalArticle

Mizuguchi, T, Nakashima, M, Kato, M, Okamoto, N, Kurahashi, H, Ekhilevitch, N, Shiina, M, Nishimura, G, Shibata, T, Matsuo, M, Ikeda, T, Ogata, K, Tsuchida, N, Mitsuhashi, S, Miyatake, S, Takata, A, Miyake, N, Hata, K, Kaname, T, Matsubara, Y, Saitsu, H & Matsumoto, N 2018, 'Loss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders', Human Molecular Genetics, vol. 27, no. 8, pp. 1421-1433. https://doi.org/10.1093/hmg/ddy052
Mizuguchi T, Nakashima M, Kato M, Okamoto N, Kurahashi H, Ekhilevitch N et al. Loss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders. Human Molecular Genetics. 2018 Apr 15;27(8):1421-1433. https://doi.org/10.1093/hmg/ddy052
Mizuguchi, Takeshi ; Nakashima, Mitsuko ; Kato, Mitsuhiro ; Okamoto, Nobuhiko ; Kurahashi, Hirokazu ; Ekhilevitch, Nina ; Shiina, Masaaki ; Nishimura, Gen ; Shibata, Takashi ; Matsuo, Muneaki ; Ikeda, Tae ; Ogata, Kazuhiro ; Tsuchida, Naomi ; Mitsuhashi, Satomi ; Miyatake, Satoko ; Takata, Atsushi ; Miyake, Noriko ; Hata, Kenichiro ; Kaname, Tadashi ; Matsubara, Yoichi ; Saitsu, Hirotomo ; Matsumoto, Naomichi. / Loss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders. In: Human Molecular Genetics. 2018 ; Vol. 27, No. 8. pp. 1421-1433.
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