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首页> 外文期刊>American Journal of Physiology >Identification and functional characterization of malignant hyperthermia mutation T1354S in the outer pore of the Cavalpha1S-subunit.
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Identification and functional characterization of malignant hyperthermia mutation T1354S in the outer pore of the Cavalpha1S-subunit.

机译：Cavalpha1S亚基外孔中恶性高热突变T1354S的鉴定和功能表征。

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摘要

To identify the genetic locus responsible for malignant hyperthermia susceptibility (MHS) in an Italian family, we performed linkage analysis to recognized MHS loci. All MHS individuals showed cosegregation of informative markers close to the voltage-dependent Ca(2+) channel (Ca(V)) alpha(1S)-subunit gene (CACNA1S) with logarithm of odds (LOD)-score values that matched or approached the maximal possible value for this family. This is particularly interesting, because so far MHS was mapped to >178 different positions on the ryanodine receptor (RYR1) gene but only to two on CACNA1S. Sequence analysis of CACNA1S revealed a c.4060A>T transversion resulting in amino acid exchange T1354S in the IVS5-S6 extracellular pore-loop region of Ca(V)alpha(1S) in all MHS subjects of the family but not in 268 control subjects. To investigate the impact of mutation T1354S on the assembly and function of the excitation-contraction coupling apparatus, we expressed GFP-tagged alpha(1S)T1354S in dysgenic (alpha(1S)-null) myotubes. Whole cell patch-clamp analysis revealed that alpha(1S)T1354S produced significantly faster activation of L-type Ca(2+) currents upon 200-ms depolarizing test pulses compared with wild-type GFP-alpha(1S) (alpha(1S)WT). In addition, alpha(1S)T1354S-expressing myotubes showed a tendency to increased sensitivity for caffeine-induced Ca(2+) release and to larger action-potential-induced intracellular Ca(2+) transients under low (
机译：为了确定一个意大利家庭的恶性高热敏感性（MHS）的遗传基因座，我们对公认的MHS基因座进行了连锁分析。所有MHS个体显示接近电压依赖性Ca（2+）通道（Ca（V））alpha（1S）-亚基基因（CACNA1S）的信息性标记共分离，且奇数对数（LOD）得分相匹配或接近这个家庭的最大可能价值。这是特别有趣的，因为到目前为止，MHS映射到了ryanodine受体（RYR1）基因上的> 178个不同位置，而CACNA1S上仅映射到了两个位置。 CACNA1S的序列分析显示c.4060A> T转换导致该家族的所有MHS受试者中Ca（V）alpha（1S）的IVS5-S6细胞外孔环区域中的氨基酸交换T1354S，但没有268个对照受试者。若要调查突变T1354S对激发-收缩偶联仪器的组装和功能的影响，我们在成胚性（alpha（1S）-无效）肌管中表达了GFP标签的alpha（1S）T1354S。全细胞膜片钳分析显示，与野生型GFP-alpha（1S）（alpha（1S）相比，alpha（1S）T1354S在200毫秒去极化测试脉冲后产生的L型Ca（2+）电流活化明显更快WT）。此外，表达α（1S）T1354S的肌管在咖啡因诱导的Ca（2+）释放敏感性增加的趋势下，在低（

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