The Experts below are selected from a list of 267 Experts worldwide ranked by ideXlab platform
Louis J. Ptáček - One of the best experts on this subject based on the ideXlab platform.
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Sodium channel mutations in Paramyotonia congenita and hyperkalemic periodic paralysis
Annals of neurology, 2004Co-Authors: Louis J. Ptáček, Al George, Rl Barchi, Launce Gouw, Hubert Kwieciński, Philip G. Mcmanis, Jerry R. Mendell, Richard J. Barohn, Margaret Robertson, Mark LeppertAbstract:Clinical and electrophysiological data have outlined a spectrum of similar yet distinct periodic paralyses, including potassium-sensitive (hyperkalemic periodic paralysis [HYPP]) and temperature-sensitive (Paramyotonia congenita [PC]) forms. Recent work has revealed that these disorders result from allelic defects in the alpha-subunit of the adult, human skeletal muscle sodium channel. We report an additional mutation, a leucine-->arginine substitution in the S3 segment of domain 4 (L1433R), that results in the PC phenotype. Five other HYPP and PC families have been ascertained, and previously reported sodium channel mutations have been identified in each. Characterization of these mutations and phenotypic variations in such families will contribute to the understanding of sodium channel structure and function relationships, as well as channel malfunction in the periodic paralyses.
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Sodium channel mutations in Paramyotonia congenita exhibit similar biophysical phenotypes in vitro
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Naibo Yang, Louis J. Ptáček, Ming Zhou, Robert L. Barchi, Richard Horn, Alfred L. GeorgeAbstract:Mutations in the skeletal muscle voltage-gated Na+ channel alpha-subunit have been found in patients with two distinct hereditary disorders of sarcolemmal excitation: hyperkalemic periodic paralysis (HYPP) and Paramyotonia congenita (PC). Six of these mutations have been functionally expressed in a heterologous cell line (tsA201 cells) using the recombinant human skeletal muscle Na+ channel alpha-subunit cDNA hSkM1. PC mutants from diverse locations in this subunit (T1313M, L1433R, R1448H, R1448C, A1156T) all exhibit a similar disturbance in channel inactivation characterized by reduced macroscopic rate, accelerated recovery, and altered voltage dependence. PC mutants had no significant abnormality in activation. In contrast, one HYPP mutation studied (T704M) has a normal inactivation rate but exhibits shifts in the midpoints of steady-state activation and inactivation along the voltage axis. These findings help to explain the phenotypic differences between HYPP and PC at the molecular and biophysical level and contribute to our understanding of Na+ channel structure and function.
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sodium channel mutations in acetazolamide responsive myotonia congenita Paramyotonia congenita and hyperkalemic periodic paralysis
Neurology, 1994Co-Authors: Louis J. Ptáček, G. Meola, Robert C. Griggs, Philip G. Mcmanis, Jerry R. Mendell, Richard J. Barohn, Rabi Tawil, C P Harris, R Spitzer, F SantiagoAbstract:Hyperkalemic periodic paralysis (hyperKPP) and Paramyotonia congenita (PC) are genetic muscle disorders sharing the common features of myotonia and episodic weakness. In hyperKPP, patient symptoms and signs are worsened by elevated serum potassium, whereas in PC, muscle cooling exacerbates the condition. There are patients in whom features of both hyperKPP and PC are present. These diseases result from molecular alterations in the adult skeletal muscle sodium channel. This report summarizes our sodium channel mutation analysis in 25 families with hyperKPP and PC. We also report the putative disease-causing mutation in acetazolamide-responsive myotonia congenita, a related disease in which myotonia is worsened by potassium but in which episodic weakness does not occur. This missense mutation (I1160V) occurs at a very highly conserved position in the sodium channel, cosegregates with the disease, and was not present in any of a large panel of normal DNAs. Electrophysiologic characterization of specific mutations will lead to better understanding of the biophysics of this voltage-gated ion channel.
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Sodium channel mutations in acetazolamide‐responsive myotonia congenita, Paramyotonia congenita, and hyperkalemic periodic paralysis
Neurology, 1994Co-Authors: Louis J. Ptáček, G. Meola, Robert C. Griggs, Philip G. Mcmanis, Jerry R. Mendell, Richard J. Barohn, Rabi Tawil, C P Harris, R Spitzer, F SantiagoAbstract:Hyperkalemic periodic paralysis (hyperKPP) and Paramyotonia congenita (PC) are genetic muscle disorders sharing the common features of myotonia and episodic weakness. In hyperKPP, patient symptoms and signs are worsened by elevated serum potassium, whereas in PC, muscle cooling exacerbates the condition. There are patients in whom features of both hyperKPP and PC are present. These diseases result from molecular alterations in the adult skeletal muscle sodium channel. This report summarizes our sodium channel mutation analysis in 25 families with hyperKPP and PC. We also report the putative disease-causing mutation in acetazolamide-responsive myotonia congenita, a related disease in which myotonia is worsened by potassium but in which episodic weakness does not occur. This missense mutation (I1160V) occurs at a very highly conserved position in the sodium channel, cosegregates with the disease, and was not present in any of a large panel of normal DNAs. Electrophysiologic characterization of specific mutations will lead to better understanding of the biophysics of this voltage-gated ion channel.
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Mutation in the S4 segment of the adult skeletal sodium channel gene in an Italian Paramyotonia congenita (PC) family
Italian journal of neurological sciences, 1994Co-Authors: V. Sansone, Louis J. Ptáček, G. Rotondo, G. MeolaAbstract:The periodic paralyses are a group of autosomal dominant muscle diseases sharing the common feature of episodic stiffness and weakness, usually occurring with muscle cooling (as in the case of Paramyotonia congenita, PC pheno-type) or changes in extracellular K+ levels resulting from various precipitating factors (hyperkalemic periodic paralysis, HYPP and hypokalemic periodic paralysis, Hypo PP).
Alfred L. George - One of the best experts on this subject based on the ideXlab platform.
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Mutant channels contribute,50 % to Na1 current in Paramyotonia congenita muscle
2015Co-Authors: Nenad Mitrovic, Frank Lehmann-horn, Alfred L. George, Holger LercheAbstract:An important question in the pathophysiology of dominantly inherited diseases, such as channelopathies, is the level of expression of the mutant protein. In our study, we address this issue by comparing the gating defects of two human muscle NaF channel mutants (R1448C and R1448P) causing Paramyotonia congenita in native muscle specimens from two patients with those of the same mutant recombinant channels expressed in human embryonic kidney (HEK-293) cells. Patch-clamp recordings of transfected HEK-293 cells revealed a pronounced slowing of the NaF current decay, a left-shifted and decreased voltage dependence of steady-state inactivation, and an increased frequency of channel reopenings for mutant compared with wild-type channels
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Ranolazine block of human Nav1.4 sodium channels and Paramyotonia congenita mutants
Channels (Austin Tex.), 2011Co-Authors: Nesrine El-bizri, Luiz Belardinelli, Alfred L. George, Kristopher M. Kahlig, John C. Shyrock, Sridharan RajamaniAbstract:The antianginal drug ranolazine exerts voltage- and use-dependent block (UDB) of several Na+ channel isoforms, including Nav1.4. We hypothesized that ranolazine will similarly inhibit the Paramyotonia congenita Nav1.4 gain-of-function mutations, R1448C, R1448H, and R1448P that are associated with repetitive action potential firing. Whole-cell Na+ current (INa) was recorded from HEK293 cells expressing the hNav1.4 WT or R1448 mutations. At a holding potential (HP) of -140 mV, ranolazine exerted UDB (10 Hz) of WT and R1448 mutations (IC50 = 59 - 71 µM). The potency for ranolazine UDB increased when the frequency of stimulation was raised to 30 Hz (IC50 = 20 - 27 uM). When the HP was changed to -70 mV to mimic the resting potential of an injured skeletal muscle fibre, the potency of ranolazine to block INa further increased; values of ranolazine IC50 for block of WT, R1448C, R1448H, and R1448P were 3.8, 0.9, 6.3, and 0.9 uM, respectively. Ranolazine (30 uM) also caused a hyperpolarizing shift in the voltage-...
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Different effects of mexiletine on two mutant sodium channels causing Paramyotonia congenita and hyperkalemic periodic paralysis
Neuromuscular disorders : NMD, 2000Co-Authors: K. Weckbecker, Frank Lehmann-horn, Alfred L. George, Holger Lerche, A. Würz, B. Mohammadi, T. Mansuroglu, Reinhard Dengler, Nenad MitrovicAbstract:Effects of the antiarrhythmic and antimyotonic drug mexiletine were studied on two sodium channel mutants causing Paramyotonia congenita (R1448H) and an overlap paramyotonic and hyperkalemic paralytic syndrome (M1360V). Channels were expressed in human embryonic kidney cells and studied electrophysiologically, using the whole-cell patch-clamp technique. Compared to the wild-type, channel, both mutants showed alterations of inactivation, i.e. slower inactivation, left shift of steady-state inactivation and faster recovery from inactivation. Mexiletine caused a significantly larger use-dependent block of the R1448H mutant when compared to M1360V and wild-type channels. This can be explained by a prolonged recovery from mexiletine block as observed for R1448H channels, since the affinity of mexiletine for the inactivated state was similar for all three clones. The use-dependent block of sodium channels by mexiletine reduces repetitive series of action potentials and therefore improves muscle stiffness in myotonic patients. The enhanced use-dependent block as seen with R1448H may explain the extraordinary therapeutic efficacy of mexiletine in most patients with Paramyotonia congenita.
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mutant channels contribute 50 to na current in Paramyotonia congenita muscle
Brain, 1999Co-Authors: Nenad Mitrovic, Alfred L. George, Reinhardt Rudel, Frank Lehmannhorn, Holger LercheAbstract:An important question in the pathophysiology of dominantly inherited diseases, such as channelopathies, is the level of expression of the mutant protein. In our study, we address this issue by comparing the gating defects of two human muscle Na+ channel mutants (R1448C and R1448P) causing Paramyotonia congenita in native muscle specimens from two patients with those of the same mutant recombinant channels expressed in human embryonic kidney (HEK-293) cells. Patch-clamp recordings of transfected HEK-293 cells revealed a pronounced slowing of the Na+ current decay, a left-shifted and decreased voltage dependence of steady-state inactivation, and an increased frequency of channel reopenings for mutant compared with wild-type channels. For R1448P channels, inactivation was almost six-fold and for R1448C it was three-fold slower than for wild-type channels. The same defects, though less pronounced, as expected for a disorder with dominant inheritance, were observed for muscle specimens from Paramyotonia congenita patients carrying these mutations. Quantitative kinetic analysis of Na+ channel inactivation in the paramyotonic muscle specimens separating wild-type from mutant channels suggested that no more than 38% of the channels in the Paramyotonia congenita muscle specimen were of the mutant type. Our data raise 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.
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functional expression of the ile693thr na channel mutation associated with Paramyotonia congenita in a human cell line
The Journal of Physiology, 1998Co-Authors: Emmanuelle Plassartschiess, Alfred L. George, L Lhuillier, B Fontaine, N TabtiAbstract:The Ile693Thr mutation of the skeletal muscle Na+ channel α-subunit is associated with an unusual phenotype of Paramyotonia congenita characterized by cold-induced muscle weakness but no stiffness. This mutation occurs in the S4-S5 linker of domain II, a region that has not been previously implicated in Paramyotonia congenita. The Ile693Thr mutation was introduced into the human skeletal muscle Na+ gene for functional expression in human embryonic kidney (HEK) cells. The currents expressed were recorded with the whole-cell voltage-clamp technique. In comparison with wild-type currents, Ile693Thr mutant currents showed a clear shift of about −9 mV in the voltage dependence of activation. In contrast to other mutations of the Na+ channel known to cause Paramyotonia congenita, the Ile693Thr mutation did not induce any significant change in the kinetics, nor in the voltage dependence, of fast inactivation. In conclusion, this study provides further evidence of the involvement of the S4-S5 linker in the voltage dependence of Na+ channel activation. The negative shift in the voltage dependence found in this mutation must be associated to other defects, plausibly an impairment of the slow inactivation, to account for the long periods of muscle weakness experienced by the patients. Mutations in the human Na+ channel α-subunit gene SCN4A have been implicated in three groups of autosomal dominant muscle disorders: hyperkalaemic periodic paralysis (hyper-PP), Paramyotonia congenita (PC) and K+-aggravated myotonia (PAM) (Lehmann-Horn & Rudel, 1996). To date, at least twenty Na+ channel mutations have been reported, all of which result in substitutions of highly conserved residues in the intracellular loops or in the transmembrane segments of the Na+ channel α-subunit (Feero et al. 1993; Ptacek et al. 1993; Plassart et al. 1994; Lehmann-Horn & Rudel, 1996). Among these mutations, nine (including the present) have been associated with Paramyotonia congenita (McClatchey et al. 1992; Ptacek et al. 1992, Plassart et al. 1996; Yang, Zhou, Ptacek, Barchi, Horn & George, 1994). Paramyotonia congenita is a myotonic disorder characterized by cold-induced muscle stiffness and weakness (Riggs & Griggs, 1979; Lehmann-Horn, Rudel & Ricker, 1993). However, the clinical variability observed within families, as well as between different families carrying the same mutation, complicates the classification of PC (Ptacek et al. 1992; Lehmann-Horn et al. 1993; Plassart et al. 1994). Recently, we identified a new Na+ channel mutation (Ile693Thr) in a French family who exhibited an unusual phenotype, classified as a variant of PC, with cold-induced weakness but no stiffness (Plassart et al. 1996). One of the patients carrying the Ile693Thr mutation presented hyperPP in addition to PC: weakness could be induced by oral intake of K+, and a vacuolar myopathy usually described in hyperPP was found in muscle biopsies. The consequences of this mutation on Na+ channel functional properties are still unknown. In the present study, the Ile693Thr mutation was transiently expressed in human embryonic kidney (HEK 293) cells and the kinetics as well as the voltage dependence of the mutant channels were studied using the whole-cell voltage-clamp technique.
Mark Leppert - One of the best experts on this subject based on the ideXlab platform.
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Sodium channel mutations in Paramyotonia congenita and hyperkalemic periodic paralysis
Annals of neurology, 2004Co-Authors: Louis J. Ptáček, Al George, Rl Barchi, Launce Gouw, Hubert Kwieciński, Philip G. Mcmanis, Jerry R. Mendell, Richard J. Barohn, Margaret Robertson, Mark LeppertAbstract:Clinical and electrophysiological data have outlined a spectrum of similar yet distinct periodic paralyses, including potassium-sensitive (hyperkalemic periodic paralysis [HYPP]) and temperature-sensitive (Paramyotonia congenita [PC]) forms. Recent work has revealed that these disorders result from allelic defects in the alpha-subunit of the adult, human skeletal muscle sodium channel. We report an additional mutation, a leucine-->arginine substitution in the S3 segment of domain 4 (L1433R), that results in the PC phenotype. Five other HYPP and PC families have been ascertained, and previously reported sodium channel mutations have been identified in each. Characterization of these mutations and phenotypic variations in such families will contribute to the understanding of sodium channel structure and function relationships, as well as channel malfunction in the periodic paralyses.
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Mutations in an S4 segment of the adult skeletal muscle sodium channel cause Paramyotonia congenita.
Neuron, 1992Co-Authors: Louis J. Ptáček, Jack E. Riggs, Robert C. Griggs, Alfred L. George, Robert L. Barchi, Margaret Robertson, Mark LeppertAbstract:The periodic paralyses are a group of autosomal dominant muscle diseases sharing a common feature of episodic paralysis. In one form, Paramyotonia congenita (PC), the paralysis usually occurs with muscle cooling. Electrophysiologic studies of muscle from PC patients have revealed temperature-dependent alterations in sodium channel (NaCh) function. This observation led to demonstration of genetic linkage of a skeletal muscle NaCh gene to a PC disease allele. We now report the use of the single-strand conformation polymorphism technique to define alleles specific to PC patients from three families. Sequencing of these alleles defined base pair changes within the same codon, which resulted in two distinct amino acid substitutions for a highly conserved arginine residue in the S4 helix of domain 4 in the adult skeletal muscle NaCh. These data establish the chromosome 17q NaCh locus as the PC gene and represent two mutations causing the distinctive, temperature-sensitive PC phenotype.
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Paramyotonia congenita and hyperkalemic periodic paralysis map to the same sodium-channel gene locus.
American journal of human genetics, 1991Co-Authors: Louis J. Ptáček, J.w. Roberts, William S. Agnew, Jackh . Petajan, James S. Trimmer, Mark LeppertAbstract:Paramyotonia congenita (PC), an autosomal dominant muscle disease, shares some clinical and electrophysiological similarities with another myotonic muscle disorder, hyperkalemic periodic paralysis (HYPP). However, clinical and electrophysiologic differences allow differentiation of the two disorders. The HYPP locus was recently shown to be linked to a skeletal muscle sodium-channel gene probe. We now report that PC maps to the same locus (LOD score 4.4, theta = 0 at assumed penetrance of .95). These linkage results, coupled with physiological data demonstrating abnormal sodium-channel function in patients with PC, implicate a sodium-channel gene as an important candidate for the site of mutation responsible for PC. Furthermore, this is strong evidence for the hypothesis that PC and HYPP are allelic disorders.
N Tabti - One of the best experts on this subject based on the ideXlab platform.
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Functional expression of the Ile693Thr Na+ channel mutation associated with Paramyotonia congenita in a human cell line.
The Journal of physiology, 1998Co-Authors: E Plassart-schiess, Al George, L Lhuillier, B Fontaine, N TabtiAbstract:1. The Ile693Thr mutation of the skeletal muscle Na+ channel alpha-subunit is associated with an unusual phenotype of Paramyotonia congenita characterized by cold-induced muscle weakness but no stiffness. This mutation occurs in the S4-S5 linker of domain II, a region that has not been previously implicated in Paramyotonia congenita. 2. The Ile693Thr mutation was introduced into the human skeletal muscle Na+ gene for functional expression in human embryonic kidney (HEK) cells. The currents expressed were recorded with the whole-cell voltage-clamp technique. 3. In comparison with wild-type currents, Ile693Thr mutant currents showed a clear shift of about -9 mV in the voltage dependence of activation. 4. In contrast to other mutations of the Na+ channel known to cause Paramyotonia congenita, the Ile693Thr mutation did not induce any significant change in the kinetics, nor in the voltage dependence, of fast inactivation. 5. In conclusion, this study provides further evidence of the involvement of the S4-S5 linker in the voltage dependence of Na+ channel activation. The negative shift in the voltage dependence found in this mutation must be associated to other defects, plausibly an impairment of the slow inactivation, to account for the long periods of muscle weakness experienced by the patients.
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functional expression of the ile693thr na channel mutation associated with Paramyotonia congenita in a human cell line
The Journal of Physiology, 1998Co-Authors: Emmanuelle Plassartschiess, Alfred L. George, L Lhuillier, B Fontaine, N TabtiAbstract:The Ile693Thr mutation of the skeletal muscle Na+ channel α-subunit is associated with an unusual phenotype of Paramyotonia congenita characterized by cold-induced muscle weakness but no stiffness. This mutation occurs in the S4-S5 linker of domain II, a region that has not been previously implicated in Paramyotonia congenita. The Ile693Thr mutation was introduced into the human skeletal muscle Na+ gene for functional expression in human embryonic kidney (HEK) cells. The currents expressed were recorded with the whole-cell voltage-clamp technique. In comparison with wild-type currents, Ile693Thr mutant currents showed a clear shift of about −9 mV in the voltage dependence of activation. In contrast to other mutations of the Na+ channel known to cause Paramyotonia congenita, the Ile693Thr mutation did not induce any significant change in the kinetics, nor in the voltage dependence, of fast inactivation. In conclusion, this study provides further evidence of the involvement of the S4-S5 linker in the voltage dependence of Na+ channel activation. The negative shift in the voltage dependence found in this mutation must be associated to other defects, plausibly an impairment of the slow inactivation, to account for the long periods of muscle weakness experienced by the patients. Mutations in the human Na+ channel α-subunit gene SCN4A have been implicated in three groups of autosomal dominant muscle disorders: hyperkalaemic periodic paralysis (hyper-PP), Paramyotonia congenita (PC) and K+-aggravated myotonia (PAM) (Lehmann-Horn & Rudel, 1996). To date, at least twenty Na+ channel mutations have been reported, all of which result in substitutions of highly conserved residues in the intracellular loops or in the transmembrane segments of the Na+ channel α-subunit (Feero et al. 1993; Ptacek et al. 1993; Plassart et al. 1994; Lehmann-Horn & Rudel, 1996). Among these mutations, nine (including the present) have been associated with Paramyotonia congenita (McClatchey et al. 1992; Ptacek et al. 1992, Plassart et al. 1996; Yang, Zhou, Ptacek, Barchi, Horn & George, 1994). Paramyotonia congenita is a myotonic disorder characterized by cold-induced muscle stiffness and weakness (Riggs & Griggs, 1979; Lehmann-Horn, Rudel & Ricker, 1993). However, the clinical variability observed within families, as well as between different families carrying the same mutation, complicates the classification of PC (Ptacek et al. 1992; Lehmann-Horn et al. 1993; Plassart et al. 1994). Recently, we identified a new Na+ channel mutation (Ile693Thr) in a French family who exhibited an unusual phenotype, classified as a variant of PC, with cold-induced weakness but no stiffness (Plassart et al. 1996). One of the patients carrying the Ile693Thr mutation presented hyperPP in addition to PC: weakness could be induced by oral intake of K+, and a vacuolar myopathy usually described in hyperPP was found in muscle biopsies. The consequences of this mutation on Na+ channel functional properties are still unknown. In the present study, the Ile693Thr mutation was transiently expressed in human embryonic kidney (HEK 293) cells and the kinetics as well as the voltage dependence of the mutant channels were studied using the whole-cell voltage-clamp technique.
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Functional expression of the Ile693Thr Na+ channel mutation associated with Paramyotonia congenita in a human cell line
The Journal of Physiology, 1998Co-Authors: E Plassart-schiess, Alfred L. George, L Lhuillier, B Fontaine, N TabtiAbstract:The Ile693Thr mutation of the skeletal muscle Na+ channel α-subunit is associated with an unusual phenotype of Paramyotonia congenita characterized by cold-induced muscle weakness but no stiffness. This mutation occurs in the S4-S5 linker of domain II, a region that has not been previously implicated in Paramyotonia congenita. The Ile693Thr mutation was introduced into the human skeletal muscle Na+ gene for functional expression in human embryonic kidney (HEK) cells. The currents expressed were recorded with the whole-cell voltage-clamp technique. In comparison with wild-type currents, Ile693Thr mutant currents showed a clear shift of about −9 mV in the voltage dependence of activation. In contrast to other mutations of the Na+ channel known to cause Paramyotonia congenita, the Ile693Thr mutation did not induce any significant change in the kinetics, nor in the voltage dependence, of fast inactivation. In conclusion, this study provides further evidence of the involvement of the S4-S5 linker in the voltage dependence of Na+ channel activation. The negative shift in the voltage dependence found in this mutation must be associated to other defects, plausibly an impairment of the slow inactivation, to account for the long periods of muscle weakness experienced by the patients. Mutations in the human Na+ channel α-subunit gene SCN4A have been implicated in three groups of autosomal dominant muscle disorders: hyperkalaemic periodic paralysis (hyper-PP), Paramyotonia congenita (PC) and K+-aggravated myotonia (PAM) (Lehmann-Horn & Rudel, 1996). To date, at least twenty Na+ channel mutations have been reported, all of which result in substitutions of highly conserved residues in the intracellular loops or in the transmembrane segments of the Na+ channel α-subunit (Feero et al. 1993; Ptacek et al. 1993; Plassart et al. 1994; Lehmann-Horn & Rudel, 1996). Among these mutations, nine (including the present) have been associated with Paramyotonia congenita (McClatchey et al. 1992; Ptacek et al. 1992, Plassart et al. 1996; Yang, Zhou, Ptacek, Barchi, Horn & George, 1994). Paramyotonia congenita is a myotonic disorder characterized by cold-induced muscle stiffness and weakness (Riggs & Griggs, 1979; Lehmann-Horn, Rudel & Ricker, 1993). However, the clinical variability observed within families, as well as between different families carrying the same mutation, complicates the classification of PC (Ptacek et al. 1992; Lehmann-Horn et al. 1993; Plassart et al. 1994). Recently, we identified a new Na+ channel mutation (Ile693Thr) in a French family who exhibited an unusual phenotype, classified as a variant of PC, with cold-induced weakness but no stiffness (Plassart et al. 1996). One of the patients carrying the Ile693Thr mutation presented hyperPP in addition to PC: weakness could be induced by oral intake of K+, and a vacuolar myopathy usually described in hyperPP was found in muscle biopsies. The consequences of this mutation on Na+ channel functional properties are still unknown. In the present study, the Ile693Thr mutation was transiently expressed in human embryonic kidney (HEK 293) cells and the kinetics as well as the voltage dependence of the mutant channels were studied using the whole-cell voltage-clamp technique.
A J Tahmoush - One of the best experts on this subject based on the ideXlab platform.
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patch clamp studies of the thr1313met mutant sodium channel causing Paramyotonia congenita
Muscle & Nerve, 2000Co-Authors: Paul T Boulos, Terry Heimanpatterson, Guillermo M Alexander, A J TahmoushAbstract:Paramyotonia congenita (PC) is an autosomal-dominant disorder due to a point mutation in the adult skeletal muscle Na channel gene. Muscle fibers from PC patients have normal membrane properties at 32°C. At 27°C, they are inexcitable, have increased Na conductance, and have a reduced resting membrane potential of −40 mV. To define the biophysical basis for the muscle membrane abnormalities, we performed patch clamp whole-cell and outside-out single Na channel studies at 22°C on cultured human muscle cells from 4 control patients and 2 sisters with PC and the thr1313met mutant Na channel. The whole-cell studies showed no difference in window currents. Unlike cells transfected with the thr1313met mutant Na channel, the inactivation time constant, τh, for PC cells was similar to control cells. For PC recordings containing long-duration single Na channel openings, mean open time was prolonged at −60, −40, and −20 mV. The long-duration Na channel openings occurred randomly with no evidence of modal gating. The number of channel openings, occurrence of late openings, and the prolonged mean open time resulted in a sustained inward Na current at −40 mV. We suggest that the biophysical marker of the thr1313met mutant Na channel is a voltage- and temperature-dependent abnormality in mutant single Na channel behavior. © 2000 John Wiley & Sons, Inc. Muscle Nerve 23: 1736–1747, 2000.
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Muscle sodium channel inactivation defect in Paramyotonia congenita with the thr1313met mutation
Neuromuscular Disorders, 1994Co-Authors: A J Tahmoush, K L Schaller, P Zhang, T Hyslop, T Heiman-patterson, J H CaldwellAbstract:Abstract Mutations of the skeletal muscle sodium (Na) channel have been reported in families with Paramyotonia congenita (PC), an autosomal dominant disorder with cold and/or exercise induced stiffness and myotonia. Functional consequences of specific Na channel mutations responsible for PC have not been described. Patch clamp recording of single Na channels were made in cultured myotubes at 22 and 34°C from a PC patient with the thr1313met mutation. Cell-attached and outside-out recordings of mutant PC channels contained long duration and late openings. The mean open time was increased and the ensemble average showed a prolonged inward Na current. This membrane depolarization could cause repetitive action potentials and the clinical syndrome.
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Muscle sodium channel inactivation defect in Paramyotonia congenita with the thr1313met mutation.
Neuromuscular disorders : NMD, 1994Co-Authors: A J Tahmoush, K L Schaller, P Zhang, T Hyslop, T Heiman-patterson, J H CaldwellAbstract:Mutations of the skeletal muscle sodium (Na) channel have been reported in families with Paramyotonia congenita (PC), an autosomal dominant disorder with cold and/or exercise induced stiffness and myotonia. Functional consequences of specific Na channel mutations responsible for PC have not been described. Patch clamp recording of single Na channels were made in cultured myotubes at 22 and 34 degrees C from a PC patient with the thr1313met mutation. Cell-attached and outside-out recordings of mutant PC channels contained long duration and late openings. The mean open time was increased and the ensemble average showed a prolonged inward Na current. This membrane depolarization could cause repetitive action potentials and the clinical syndrome.