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. 2000 Aug 15;97(17):9549-54.
doi: 10.1073/pnas.97.17.9549.

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

K Jurkat-Rott  1 , N Mitrovic, C Hang, A Kouzmekine, P Iaizzo, J Herzog, H Lerche, S Nicole, J Vale-Santos, D Chauveau, B Fontaine, F Lehmann-Horn
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Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current

K Jurkat-Rott et al. Proc Natl Acad Sci U S A. .

"VSports手机版" Abstract

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 alpha 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 alpha 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. VSports手机版.

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Figure 1
Figure 1
Pedigree of family HypoPP106 and genetic map of the SCN4A locus on chromosome 17q. Patients are represented by filled symbols and unaffected individuals by open symbols (square = males; circles = females). The haplotype segregating with the disease is boxed. A marker map is on the left below the pedigree. (Lower) A polyacrylamide gel electrophoresis of the C-2015-G allele-specific PCR product (265 bp) shows cosegregation of the mutation encoding Arg-672→Gly without recombinants. The additional constant band of 386 bp is the PCR product of SCN4A exon 6 in the same reaction mix, demonstrating DNA integrity of each sample.
Figure 2
Figure 2
Pedigrees of families HypoPP6, HypoPP29, HypoPP18, and HypoPP105. Symbols and markers are as in Fig. 1. In addition to the allele-specific marker shown for C-2015-G for HypoPP6, an allele-specific marker for the G-2016-A transition in exon 12 predicting Arg-672→His was used for families HypoPP29, HypoPP18, and HypoPP105 of 266 bp. The control band of 386 bp was SCN4A exon 6 in all cases.
Figure 3
Figure 3
Sodium currents elicited by a family of 10-ms lasting depolarizations from a −140 mV holding potential to voltages ranging from −90 to +20 mV in 5-mV steps were recorded from tsA-201 cells expressing WT, Arg-672→His, and Arg-672→Gly α subunit channels. The maximum peaks were normalized to identical amplitudes. (B) Corresponding peak current-voltage relationships (n = 5–7) normalized to maximum (=100%). (C) Voltage dependence of the activation time constants is plotted against voltage steps. The kinetics of activation were estimated by determining the rise time between 10% and 90% (n = 5–9). (D) Deactivation kinetics measured at 15°C. Cells held at −140 mV were depolarized for 500 μs to +20 mV before stepping back to test potentials shown (n = 3–5).
Figure 4
Figure 4
(A) Steady-state inactivation was determined from a holding potential of −160 mV by using a series of 300-ms prepulses from −160 to +27.5 mV in 7.5-mV increments before the test pulse to −20 mV. Note that all measurements were performed in chloride-reduced pipette solution containing fluoride and yielding highly negative Vh0.5. (B) Voltage dependence of time constants of fast inactivation time constants, τh, is given for both mutants and WT (n = 6–9). (C) Recovery from inactivation for a holding potential of −120 mV was determined by a 100-ms depolarization to −20 mV followed by a variable-duration return to −120 mV. (D) Representative action potentials from a muscle fiber segment of the HypoPP6 patient compared to those of a normal control. They were elicited from various holding potentials by a short depolarizing pulse. Note the slower rise and fall for HypoPP.
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References (V体育安卓版)

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