並列タイトル等Kir2.1に新規ミスセンス変異（L94P）を認める常染色体劣性遺伝形式のAndersen-Tawil症候群
学位博士(医学)
Philosophy in Medical Science
一般注記Aim: Dominant negative mutations of the inwardly rectifying K+ channel Kir2.1 cause Andersen-Tawil syndrome, an autosomal dominant disorder. Here, we identified a novel Kir2.1 mutation causing autosomal recessive ATS, and explored the underlying mechanism.Methods: We sequenced the coding region of KCJN2. We assessed protein subcellular localization by transfecting cells with Kir2.1-enhanced green fluorescent protein fusions and observing them by confocal microscopy. We measured K+ currents using patch clamping. Results: We identified the novel Kir2.1 missense mutation L94P. L94P-EGFP was barely detected at the plasma membrane, in contrast to WT-EGFP and L94PEGFP+WT. The excitability of L94P-expressing cells was decreased compared with that of WT-expressing cells and L94P+WT-expressing cells (p < 0.001). Conclusions: Most L94P mutant Kir2.1 fails to reach the plasma membrane, but heterotetrameric channels comprising L94P+WT can traffic normally to the plasma membrane and generate currents. The L94P mutation is transmitted as an autosomal recessive trait.
Ikuko Takeda, Tetsuya Takahashi, Hiroki Ueno, Hiroyuki Morino, Kazuhide Ochi, Takeshi Nakamura, Naohisa Hosomi, Hideshi Kawakami, Kouichi Hashimoto and Masayasu Matsumoto; Autosomal recessive Andersen-Tawil syndrome with a novel mutation L94P in Kir2.1; Neurology and Clinical Neuroscience, Volume 1, Issue 4, pages 131-137, July 2013 (doi: 10.1111/ncn3.38)
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