Paramyotonia congenita: The R1448P Na+ channel mutation in adult human skeletal muscle

  title={Paramyotonia congenita: The R1448P Na+ channel mutation in adult human skeletal muscle},
  author={Holger Lerche and Nenad Mitrovi{\'c} and Victor Dubowitz and Frank Lehmann-Horn},
  journal={Annals of Neurology},
Twitch force and Na+ currents were investigated in a muscle biopsy specimen from a patient with paramyotonia congenita carrying the dominant Arg‐1448‐Pro mutation in the skeletal muscle sodium channel. Cooling of the muscle fibers caused sustained membrane depolarization that resulted in reduced twitch force. Membrane repolarization, produced by a K+ channel opener, partly prevented and antagonized the drop in twitch force. Patch‐clamp recordings on sarcolemmal blebs revealed a distinctly… 

Patch clamp studies of the Thr1313met mutant sodium channel causing paramyotonia congenita

It is suggested that the biophysical marker of the thr1313met mutant Na channel is a voltage‐ and temperature‐dependent abnormality in mutant single Na channel behavior.

Mutant channels contribute <50% to Na+ current in paramyotonia congenita muscle.

Comparing the gating defects of two human muscle Na+ channel mutants causing paramyotonia congenita in native muscle specimens from two patients with those of the same mutant recombinant channels expressed in human embryonic kidney cells raises the possibility that variability in the ratio of mutant to wild-type Na+ channels in the muscle membrane has an impact on the clinical severity of the phenotype.

Hyperkalemic periodic paralysis M1592V mutation modifies activation in human skeletal muscle Na+ channel.

The functional properties of the M1592V mutant resemble those of the previously characterized HPP T704M mutant, both clinically similar phenotypes arise from mutations located at a distance from the putative voltage sensor of the channel.

N1366S mutation of human skeletal muscle sodium channel causes paramyotonia congenita

It is demonstrated that N1366S is a disease‐causing mutation and that the temperature‐sensitive alteration of N1365S channel activity may be responsible for the pronounced paramyotonia congenita symptoms of these patients.

Effects of temperature and mexiletine on the F1473S Na+ channel mutation causing paramyotonia congenita

It is suggested that therelative effectiveness of mexiletine is associated with the degree of abnormal channel inactivation and that the relative binding affinity of meXiletines is not substantially different between the mutations or the WT.

A novel sodium channel mutation causing a hyperkalemic paralytic and paramyotonic syndrome with variable clinical expressivity

The results are remarkable with respect to the lack of complete penetrance usually seen with sodium channelopathies and the site of mutation that was formerly not thought to be involved in channel inactivation.

Characterization of a new sodium channel mutation at arginine 1448 associated with moderate paramyotonia congenita in humans

The data show that the defects observed in the sodium channel function could well explain the onset of the paramyotonia congenita in this family and emphasize the role of segment S4 of domain IV in sodium channel inactivation.

Biophysical characterization of M1476I, a sodium channel founder mutation associated with cold‐induced myotonia in French Canadians

The data suggest that mexiletine could be used as a therapeutic for patients carrying the M1476I mutation of Nav1.4, which causes potassium‐aggravated myotonia in a French Canadian population of the Saguenay‐Lac‐Saint‐Jean region of Quebec.

Reduced muscle‐fiber conduction but normal slowing after cold exposure in paramyotonia congenita

Results indicate that, in these PC patients, mutant and wild‐type sodium channels respond equally to cold exposure, and MFCV is abnormal in these patients, but the aggravation of muscle stiffness cannot be explained by an abnormal sarcolemmal response to cold.

Sodium Channel Myotonia in the 11160V Mutant

The skeletal muscle sodium channel mutant 11160V cosegregates with a disease phenotype producing myotonic discharges that are worsened by elevated K+ levels but unaffected by cooling.



Sodium channel mutations in paramyotonia congenita exhibit similar biophysical phenotypes in vitro.

  • N. YangS. Ji A. George
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1994
Findings help to explain the phenotypic differences between HYPP and PC at the molecular and biophysical level and contribute to the understanding of Na+ channel structure and function.

Membrane defects in paramyotonia congenita with and without myotonia in a warm environment

Analysis of the membrane current densities using voltage clamps with 3 microelectrodes revealed that in paramyotonic patients at 37°C all component conductances were normal, except for a decreased CI conductance in the patient who had myotonia in a warm environment, which explains the clinical symptoms of weakness and paralysis.

Membrane defects in paramyotonia congenita (eulenburg)

The previous conclusion that the Cl conductance at 27°C was also increased when TTX was present was not confirmed and the Cl permeability was shown to be normal even in the cold.

Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III‐IV linker.

Electrophysiological and molecular genetic studies strongly suggest that three dominant point mutations discovered at the same nucleotide position of the SCN4A gene encoding the adult skeletal muscle Na+ channel alpha‐subunit cause myotonia.

Adynamia episodica hereditaria with myotonia: A non‐inactivating sodium current and the effect of extracellular pH

Lowering of the extracellular pH did not influence the resting potential, but it effectively antagonized or prevented the paralytic effect of high [K]e by changing the inactivation characteristics of the sodium channels.

Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis

Five other HYPP and PC families have been ascertained, and previously reported sodium channel mutations have been identified in each, and an additional mutation is reported, a leucine ‐ arginine substirution in the ss segment of domain 4 (L1433R), that results in the PC phenotype.

K(+)‐aggravated myotonia: destabilization of the inactivated state of the human muscle Na+ channel by the V1589M mutation.

The results suggest that the mutation increases the probabilities for channel transitions from the inactivated to the closed and the opened states and the aggravation of myotonia seen in patients during increased serum K+ may arise from the associated membrane depolarization which favours the occurrence of late openings in the mutant channel.