先天性甲状腺機能低下症患者に認めたTSH受容体変異V711FfsX18を解析した。本変異体はプロテアソーム依存的なタンパク質分解を受けるが, その説明として(1) C末端側正常54残基の喪失(2) C末端への17残基異常配列の付加の2つの説明を考えた。54残基欠失のみ生じる人工変異体V711XのcAMP産生能は保たれており(1)は否定的であった。また, 緑色蛍光たんぱく質とルシフェラーゼたんぱく質にそれぞれ異常配列を付加したところ, いずれも著明な活性低下を観察した。以上は(2)を支持してあり, 変異の影響で付加された17残基の異常配列がV711Ffsx18のたんぱく質不安定性の原因と結論した。
We analyzed a TSH receptor mutation V711FfsX18, which was observed in a patient with congenital hypothyroidism. This mutation was subject to proteasome-dependent protein degradation. Two models were considered as a explanation for the protein instability of the mutation: Model 1, Loss of intact 54 aa C-terminal sequence; Model 2, Acquisition of frame-shifted 17 aa sequence. The result of cAMP-generating activity of the V711X mutation, which was comparable to wildtype, excluded the Model 1. When the 17-aa sequence was fused to the green fluorescent protein or the luciferase protein, remarkable reduction in their activities were shown. Based on these observations, we concluded that acquisition of 17-aa frame-shifted sequence causes the protein instability of the V711FfsX TSH receotor mutation.

研究種目 : 若手研究(B)
研究期間 : 2012～2014
課題番号 : 24791087
研究分野 : 小児内分泌学