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Case Reports
. 2018 Apr 15;27(8):1421-1433.
doi: 10.1093/hmg/ddy052.

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

Takeshi Mizuguchi  1 , Mitsuko Nakashima  2 , Mitsuhiro Kato  3 , Nobuhiko Okamoto  4 , Hirokazu Kurahashi  5 , Nina Ekhilevitch  6 , Masaaki Shiina  7 , Gen Nishimura  8 , Takashi Shibata  9 , Muneaki Matsuo  10 , Tae Ikeda  11 , Kazuhiro Ogata  7 , Naomi Tsuchida  1 , Satomi Mitsuhashi  1 , Satoko Miyatake  1   12 , Atsushi Takata  1 , Noriko Miyake  1 , Kenichiro Hata  13 , Tadashi Kaname  14 , Yoichi Matsubara  15   16 , Hirotomo Saitsu  2 , Naomichi Matsumoto  1
Affiliations
Case Reports

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

Takeshi Mizuguchi et al. Hum Mol Genet. .

Abstract

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.

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