Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current

被引:191
作者
Jurkat-Rott, K
Mitrovic, N
Hang, C
Kouzmekine, A
Iaizzo, P
Herzog, J
Lerche, H
Nicole, S
Vale-Santos, J
Chauveau, D
Fontaine, B
Lehmann-Horn, F
机构
[1] Univ Ulm, Dept Appl Physiol, D-89081 Ulm, Germany
[2] Univ Ulm, Dept Neurol, D-89081 Ulm, Germany
[3] Univ Minnesota, Dept Anesthesiol, Minneapolis, MN 55455 USA
[4] Univ Munich, Dept Neurol, D-8000 Munich, Germany
[5] INSERM, Paris, France
[6] Fac Med, Federat Neurol, Paris, France
[7] Grp Hosp Pitie Salpetriere, F-75634 Paris, France
[8] Dept Neurol, Lisbon, Portugal
[9] Grp Hosp Necker Enfants Malades, Dept Nephrol, F-75013 Paris, France
关键词
channelopathy; molecular genetics; functional expression; muscle disease;
D O I
10.1073/pnas.97.17.9549
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The pathomechanism of familial hypokalemic periodic paralysis (HypoPP) is a mystery, despite knowledge of the underlying dominant point mutations in the dihydropyridine receptor (DHPR) voltage sensor. In five HypoPP families without DHPR gene defects, we identified two mutations, Arg-672-->His and -->Gly, in the voltage sensor of domain 2 of a different protein: the skeletal muscle sodium channel Lu subunit, known to be responsible for hereditary muscle diseases associated with myotonia. Excised skeletal muscle fibers from a patient heterozygous for Arg-672-->Gly displayed depolarization and weakness in low-potassium extracellular solution. Slowing and smaller size of action potentials were suggestive of excitability of the wild-type channel population only. Heterologous expression of the two sodium channel mutations revealed a 10-mV left shift of the steady-state fast inactivation curve enhancing inactivation and a sodium current density that was reduced even at potentials at which inactivation was removed. Decreased current and small action potentials suggested a low channel protein density. The alterations are decisive for the pathogenesis of episodic muscle weakness by reducing the number of excitable sodium channels particularly at sustained membrane depolarization. The results prove that SCN4A, the gene encoding the sodium channel cr subunit of skeletal muscle is responsible for HypoPP-2 which does not differ clinically from DHPR-HypoPP. HypoPP-2 represents a disease caused by enhanced channel inactivation and current reduction showing no myotonia.
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收藏
页码:9549 / 9554
页数:6
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