Malignant-hyperthermia susceptibility is associated with a mutation of the alpha(1)-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle
Malignant-hyperthermia susceptibility is associated with a mutation of the alpha(1)-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle
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DOI：
10.1086/515454
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发表时间：
1997-06-01
影响因子：
9.8
通讯作者：
Lunardi, J
中科院分区：
文献类型：
--
作者：
Monnier, N;Procaccio, V;Lunardi, J
恶性高热易感性（MHS）具有遗传异质性。然而，除了MHS 1位点，它对应于骨骼肌兰尼碱受体（RYR 1），并已被描述的几个突变，没有直接的分子证据，在另一个基因突变已被报道到目前为止。在这项研究中，我们表明，CACNL 1A 3基因编码的α 1-亚基的人骨骼肌二氢吡啶敏感的L型电压依赖性钙通道（VDCC）代表一个新的MHS基因座，并负责在一个大的法国家庭的疾病。用CACLN 1A 3基因的基因内多态性微卫星标记进行的连锁分析在重组分数为0时产生了4.38的两点LOD分数。对CACLN 1A 3基因编码区的序列分析表明，在残基1086处存在Arg-His取代，这是由A转换为G3333引起的，其与家族中的MHS表型完全分离。与先前报道的在低钾型周期性麻痹患者中发现的突变相比，该突变定位于人骨骼肌VDCC的al-亚基的非常不同的部分，并且这两种疾病可能在等位基因疾病方面进行讨论。本报告是第一个直接证据表明，骨骼肌VDCC参与MHS，它表明骨骼肌VDCC和骨骼肌肌浆网中的ryanodine受体之间的直接相互作用。
Malignant hyperthermia susceptibility (MHS) is characterized by genetic heterogeneity. However, except for the MHS1 locus, which corresponds to the skeletal muscle ryanodine receptor (RYR1) and for which several mutations have been described, no direct molecular evidence for a mutation in another gene has been reported so far. In this study we show that the CACNL1A3 gene encoding the alpha 1-subunit of the human skeletal muscle dihydropyridine-sensitive L-type voltage-dependent calcium channel (VDCC) represents a new MHS locus and is responsible for the disease in a large French family. Linkage analysis performed with an intragenic polymorphic microsatellite marker of the CACLN1A3 gene generated a two-point LOD score of 4.38 at a recombinant fraction of 0. Sequence analysis of the coding region of the CACLN1A3 gene showed the presence of an Arg-His substitution at residue 1086, resulting from the transition of A for G3333, which segregates perfectly with the MHS phenotype in the family. The mutation is localized in a very different part of the al-subunit of the human skeletal muscle VDCC, compared with previously reported mutations found in patients with hypokalemic periodic paralysis, and these two diseases might be discussed in terms of allelic diseases. This report is the first direct evidence that the skeletal muscle VDCC is involved in MHS, and it suggests a direct interaction between the skeletal muscle VDCC and the ryanodine receptor in the skeletal muscle sarcoplasmic reticulum.