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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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identification of a mutation in the gene causing Hyperkalemic Periodic Paralysis
Cell, 1991Co-Authors: Louis J. Ptáček, Mark Leppert, Robert C. Griggs, Margaret Robertson, Rabi Tawil, Alfred L. George, Roland G Kallen, Robert L BarchiAbstract:DNA from seven unrelated patients with Hyperkalemic Periodic Paralysis (HYPP) was examined for mutations in the adult skeletal muscle sodium channel gene (SCN4A) known to be genetically linked to the disorder. Single-strand conformation polymorphism analysis revealed aberrant bands that were unique to three of these seven patients. All three had prominent fixed muscle weakness, while the remaining four did not. Sequencing the aberrant bands demonstrated the same C to T transition in all three unrelated patients, predicting substitution of a highly conserved threonine residue with a methionine in a membrane-spanning segment of this sodium channel protein. The observation of a distinct mutation that cosegregates with HYPP in two families and appears as a de novo mutation in a third establishes SCN4A as the HYPP gene. Furthermore, this mutation is associated with a form of HYPP in which fixed muscle weakness is seen.
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analysis in a large Hyperkalemic Periodic Paralysis pedigree supports tight linkage to a sodium channel locus
American Journal of Human Genetics, 1991Co-Authors: Louis J. Ptáček, William S. Agnew, James S. Trimmer, Frank H Tyler, Mark LeppertAbstract:Abstract Hyperkalemic Periodic Paralysis (HYPP) is an autosomal dominant muscle disease with electrophysiological abnormalities suggesting a defect in a voltage-gated sodium channel (NaCh) gene. A human NaCh gene was recently shown to cosegregate with the disease allele in a family with HYPP. Using an independent clone, we have demonstrated close genetic linkage between an NaCh gene and the HYPP locus in another family. With physiological data demonstrating abnormal NaCh function in HYPP patients, the absence of any obligate recombinations in the two families strengthens the argument that this NaCh gene is the site of the defect in this disorder.
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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.
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 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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identification of a mutation in the gene causing Hyperkalemic Periodic Paralysis
Cell, 1991Co-Authors: Louis J. Ptáček, Mark Leppert, Robert C. Griggs, Margaret Robertson, Rabi Tawil, Alfred L. George, Roland G Kallen, Robert L BarchiAbstract:DNA from seven unrelated patients with Hyperkalemic Periodic Paralysis (HYPP) was examined for mutations in the adult skeletal muscle sodium channel gene (SCN4A) known to be genetically linked to the disorder. Single-strand conformation polymorphism analysis revealed aberrant bands that were unique to three of these seven patients. All three had prominent fixed muscle weakness, while the remaining four did not. Sequencing the aberrant bands demonstrated the same C to T transition in all three unrelated patients, predicting substitution of a highly conserved threonine residue with a methionine in a membrane-spanning segment of this sodium channel protein. The observation of a distinct mutation that cosegregates with HYPP in two families and appears as a de novo mutation in a third establishes SCN4A as the HYPP gene. Furthermore, this mutation is associated with a form of HYPP in which fixed muscle weakness is seen.
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analysis in a large Hyperkalemic Periodic Paralysis pedigree supports tight linkage to a sodium channel locus
American Journal of Human Genetics, 1991Co-Authors: Louis J. Ptáček, William S. Agnew, James S. Trimmer, Frank H Tyler, Mark LeppertAbstract:Abstract Hyperkalemic Periodic Paralysis (HYPP) is an autosomal dominant muscle disease with electrophysiological abnormalities suggesting a defect in a voltage-gated sodium channel (NaCh) gene. A human NaCh gene was recently shown to cosegregate with the disease allele in a family with HYPP. Using an independent clone, we have demonstrated close genetic linkage between an NaCh gene and the HYPP locus in another family. With physiological data demonstrating abnormal NaCh function in HYPP patients, the absence of any obligate recombinations in the two families strengthens the argument that this NaCh gene is the site of the defect in this disorder.
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Paramyotonia Congenita andHyperkalemic Periodic Paralysis MaptotheSameSodium-Channel GeneLocus
1991Co-Authors: Louis J. Ptáček, William S. Agnew, Johnw . Roberts, Jackh . PetajanAbstract:Summary Paramyotonia congenita (PC), an autosomal dominant muscle disease, shares some clinical andelectrophysiological similarities withanother myotonic muscle disorder, Hyperkalemic Periodic Paralysis (HYPP). However,clinical andelectrophysiologic differences allow differentiation ofthetwo disorders. TheHYPPlocus was recently shown tobelinked toaskeletal muscle sodium-channel geneprobe. We now reportthat PCmaps tothesame locus (LODscore4.4, 0 = 0atassumed penetranceof.95). Theselinkage results, coupled with physiological datademonstrating abnormal sodium-channel function inpatients withPC,implicate a sodium-channel gene asan important candidate forthesite ofmutation responsible forPC.Furthermore, this isstrongevidence forthehypothesis that PCandHYPPareallelic disorders.
Lawrence J. Hayward - One of the best experts on this subject based on the ideXlab platform.
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physiological basis for muscle stiffness and weakness in a knock in m1592v mouse model of Hyperkalemic Periodic Paralysis
Physiological Reports, 2015Co-Authors: Shiemaa Khogali, Lawrence J. Hayward, Brooke Lucas, Tarek Ammar, Danica Dejong, Michael Barbalinardo, Jeanmarc RenaudAbstract:Abstract The mechanisms responsible for the onset and progressive worsening of episodic muscle stiffness and weakness in Hyperkalemic Periodic Paralysis (HyperKPP) are not fully understood. Using a knock‐in HyperKPP mouse model harboring the M1592V Na V 1.4 channel mutant, we interrogated changes in physiological defects during the first year, including tetrodotoxin‐sensitive Na + influx, hindlimb electromyographic (EMG) activity and immobility, muscle weakness induced by elevated [K + ]e, myofiber‐type composition, and myofiber damage. In situ EMG activity was greater in HyperKPP than wild‐type gastrocnemius, whereas spontaneous muscle contractions were observed in vitro. We suggest that both the greater EMG activity and spontaneous contractions are related to periods of hyperexcitability during which fibers generate action potentials by themselves in the absence of any stimulation and that these periods are the cause of the muscle stiffness reported by patients. HyperKPP muscles had a greater sensitivity to the K + ‐induced force depression than wild‐type muscles. So, an increased interstitial K + concentration locally near subsets of myofibers as a result of the hyperexcitability likely produced partial loss of force rather than complete Paralysis. Na V 1.4 channel protein content reached adult level by 3 weeks postnatal in both wild type and HyperKPP and apparent symptoms did not worsen after the first month of age suggesting (i) that the phenotypic behavior of M1592V HyperKPP muscles results from defective function of mutant Na V 1.4 channels rather than other changes in protein expression after the first month and (ii) that the lag in onset during the first decade and the progression of human HyperKPP symptoms during adolescence are a function of Na V 1.4 channel content.
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understanding the physiology of the asymptomatic diaphragm of the m1592v Hyperkalemic Periodic Paralysis mouse
The Journal of General Physiology, 2015Co-Authors: Tarek Ammar, Lawrence J. Hayward, Wei Lin, Amanda Higgins, Jeanmarc RenaudAbstract:The diaphragm muscle of Hyperkalemic Periodic Paralysis (HyperKPP) patients and of the M1592V HyperKPP mouse model rarely suffers from the myotonic and paralytic symptoms that occur in limb muscles. Enigmatically, HyperKPP diaphragm expresses the mutant NaV1.4 channel and, more importantly, has an abnormally high Na+ influx similar to that in extensor digitorum longus (EDL) and soleus, two hindlimb muscles suffering from the robust HyperKPP abnormalities. The objective was to uncover the physiological mechanisms that render HyperKPP diaphragm asymptomatic. A first mechanism involves efficient maintenance of resting membrane polarization in HyperKPP diaphragm at various extracellular K+ concentrations compared with larger membrane depolarizations in HyperKPP EDL and soleus. The improved resting membrane potential (EM) results from significantly increased Na+ K+ pump electrogenic activity, and not from an increased protein content. Action potential amplitude was greater in HyperKPP diaphragm than in HyperKPP soleus and EDL, providing a second mechanism for the asymptomatic behavior of the HyperKPP diaphragm. One suggested mechanism for the greater action potential amplitude is lower intracellular Na+ concentration because of greater Na+ K+ pump activity, allowing better Na+ current during the action potential depolarization phase. Finally, HyperKPP diaphragm had a greater capacity to generate force at depolarized EM compared with wild-type diaphragm. Action potential amplitude was not different between wild-type and HyperKPP diaphragm. There was also no evidence for an increased activity of the Na+–Ca2+ exchanger working in the reverse mode in the HyperKPP diaphragm compared with the wild-type diaphragm. So, a third mechanism remains to be elucidated to fully understand how HyperKPP diaphragm generates more force compared with wild type. Although the mechanism for the greater force at depolarized resting EM remains to be determined, this study provides support for the modulation of the Na+ K+ pump as a component of therapy to alleviate weakness in HyperKPP.
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contractile abnormalities of mouse muscles expressing Hyperkalemic Periodic Paralysis mutant nav1 4 channels do not correlate with na influx or channel content
Physiological Genomics, 2014Co-Authors: Brooke Lucas, Lawrence J. Hayward, Tarek Ammar, Shiemaa Khogali, Danica Dejong, Michael Barbalinardo, Cameron Nishi, Jeanmarc RenaudAbstract:Hyperkalemic Periodic Paralysis (HyperKPP) is characterized by myotonic discharges that occur between episodic attacks of Paralysis. Individuals with HyperKPP rarely suffer respiratory distress eve...
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lessons learned from muscle fatigue implications for treatment of patients with Hyperkalemic Periodic Paralysis
Recent Patents on Biotechnology, 2012Co-Authors: Jeanmarc Renaud, Lawrence J. HaywardAbstract:Hyperkalemic Periodic Paralysis (HyperKPP) is a disease characterized by periods of myotonic discharges and paralytic attacks causing weakness, the latter associated with increases in plasma [K(+)]. The myotonic discharge is due to increased Na(+) influx through defective Na(+) channels that triggers generation of several action potentials. The subsequent increase in extracellular K(+) concentration causes excessive membrane depolarization that inactivates Na(+) channels triggering the Paralysis. None of the available treatments is fully effective. This paper reviews the capacity of Na(+) K(+)ATPase pumps, KATP and ClC-1 Cl(-) channels in improving membrane excitability during muscle activity and how using these three membrane components we can study future and more effective treatments for HyperKPP patients. The review of current patents related to HyperKPP reinforces the need of novel approaches for the treatment of this channelopathy.
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na k pump stimulation improves contractility in isolated muscles of mice with Hyperkalemic Periodic Paralysis
The Journal of General Physiology, 2011Co-Authors: Torben Clausen, Ole Baekgaard Nielsen, Johannes D Clausen, Thomas Holm Pedersen, Lawrence J. HaywardAbstract:In patients with Hyperkalemic Periodic Paralysis (HyperKPP), attacks of muscle weakness or Paralysis are triggered by K+ ingestion or rest after exercise. Force can be restored by muscle work or treatment with β2-adrenoceptor agonists. A missense substitution corresponding to a mutation in the skeletal muscle voltage-gated Na+ channel (Nav1.4, Met1592Val) causing human HyperKPP was targeted into the mouse SCN4A gene (mutants). In soleus muscles prepared from these mutant mice, twitch, tetanic force, and endurance were markedly reduced compared with soleus from wild type (WT), reflecting impaired excitability. In mutant soleus, contractility was considerably more sensitive than WT soleus to inhibition by elevated [K+]o. In resting mutant soleus, tetrodotoxin (TTX)-suppressible 22Na uptake and [Na+]i were increased by 470 and 58%, respectively, and membrane potential was depolarized (by 16 mV, P < 0.0001) and repolarized by TTX. Na+,K+ pump–mediated 86Rb uptake was 83% larger than in WT. Salbutamol stimulated 86Rb uptake and reduced [Na+]i both in mutant and WT soleus. Stimulating Na+,K+ pumps with salbutamol restored force in mutant soleus and extensor digitorum longus (EDL). Increasing [Na+]i with monensin also restored force in soleus. In soleus, EDL, and tibialis anterior muscles of mutant mice, the content of Na+,K+ pumps was 28, 62, and 33% higher than in WT, respectively, possibly reflecting the stimulating effect of elevated [Na+]i on the synthesis of Na+,K+ pumps. The results confirm that the functional disorders of skeletal muscles in HyperKPP are secondary to increased Na+ influx and show that contractility can be restored by acute stimulation of the Na+,K+ pumps. Calcitonin gene-related peptide (CGRP) restored force in mutant soleus but caused no detectable increase in 86Rb uptake. Repeated excitation and capsaicin also restored contractility, possibly because of the release of endogenous CGRP from nerve endings in the isolated muscles. These observations may explain how mild exercise helps locally to prevent severe weakness during an attack of HyperKPP.
Stephen C. Cannon - One of the best experts on this subject based on the ideXlab platform.
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A proposed mutation, Val781Ile, associated with Hyperkalemic Periodic Paralysis and cardiac dysrhythmia is a benign polymorphism
Annals of Neurology, 1997Co-Authors: Donnella S. Green, Lawrence J. Hayward, Alfred L. George, Stephen C. CannonAbstract:Twenty different point mutations have been identified in the gene coding for the α subunit of the adult skeletal muscle sodium channel in families with Hyperkalemic Periodic Paralysis, paramyotonia congenita, and the potassium-aggravated myotonias. One novel mutation (Val781Ile) was reported in an adopted boy with potassium-sensitive weakness and cardiac dysrhythmia. The confidence in establishing this rare amino acid substitution as a causative mutation was limited by the absence of family members for segregation analysis. Functional expression studies herein show that Val781Ile is most likely a benign polymorphism and not a disese-associated mutation.
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sodium channel inactivation is impaired in equine Hyperkalemic Periodic Paralysis
Journal of Neurophysiology, 1995Co-Authors: Stephen C. Cannon, Lawrence J. Hayward, J Beech, Robert H BrownAbstract:1. Equine Hyperkalemic Periodic Paralysis (E-HPP) is a dominantly inherited disorder of muscle that causes recurrent episodes of stiffness (myotonia) and weakness in association with elevated serum K+. Affected horses carry a mutant allele of the skeletal muscle isoform of the Na channel alpha-subunit. To understand how this mutation may cause the disease phenotype, the functional defect in Na channel behavior was defined physiologically by recording unitary currents from cell-attached patches on normal and affected equine myotubes. 2. The presence of the mutation was confirmed in our cell line by restriction digest of polymerase chain reaction (PCR)-amplified genomic DNA. Myotubes from the affected horse were heterozygous for the point mutation that codes for a Phe to Leu substitution in S3 of domain IV. This assay provides a rapid technique to screen for the mutation in horses at risk. 3. The primary physiological defect in mutant Na channels was an impairment of inactivation. This defect was manifest as bursts of persistent activity during which the channel closed and reopened throughout a maintained depolarization. Disrupted inactivation slowed the decay of the ensemble-averaged current and produced an eightfold increase in the steady-state open probability measured at the end of a 40-ms pulse. This point mutation identifies a new region of the alpha subunit that is important for rapid inactivation of the channel. 4. The persistent Na current was produced by a distinct mode of gating. Failure of a mutant channel to inactivate was infrequent and occurred in groups of consecutive trials.(ABSTRACT TRUNCATED AT 250 WORDS)
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a sodium channel defect in Hyperkalemic Periodic Paralysis potassium induced failure of inactivation
Neuron, 1991Co-Authors: Stephen C. Cannon, Robert H Brown, David P CoreyAbstract:Hyperkalemic Periodic analysis (HPP) is an autosomal dominant disorder characterized by episodic weakness lasting minutes to days in association with a mild elevation in serum K+. In vitro measurements of whole-cell currents in HPP muscle have demonstrated a persistent, tetrodotoxin-sensitive Na+ current, and we have recently shown by linkage analysis that the Na+ channel alpha subunit gene may contain the HPP mutation. In this study, we have made patch-clamp recordings from cultured HPP myotubes and found a defect in the normal voltage-dependent inactivation of Na+ channels. Moderate elevation of extracellular K+ favors an aberrant gating mode in a small fraction of the channels that is characterized by persistent reopenings and prolonged dwell times in the open state. The Na+ current, through noninactivating channels, may cause the skeletal muscle weakness in HPP by depolarizing the cell, thereby inactivating normal Na+ channels, which are then unable to generate an action potential. Thus the dominant expression of HPP is manifest by inactivation of the wild-type Na+ channel through the influence of the mutant gene product on membrane voltage.
Margaret Robertson - 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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identification of a mutation in the gene causing Hyperkalemic Periodic Paralysis
Cell, 1991Co-Authors: Louis J. Ptáček, Mark Leppert, Robert C. Griggs, Margaret Robertson, Rabi Tawil, Alfred L. George, Roland G Kallen, Robert L BarchiAbstract:DNA from seven unrelated patients with Hyperkalemic Periodic Paralysis (HYPP) was examined for mutations in the adult skeletal muscle sodium channel gene (SCN4A) known to be genetically linked to the disorder. Single-strand conformation polymorphism analysis revealed aberrant bands that were unique to three of these seven patients. All three had prominent fixed muscle weakness, while the remaining four did not. Sequencing the aberrant bands demonstrated the same C to T transition in all three unrelated patients, predicting substitution of a highly conserved threonine residue with a methionine in a membrane-spanning segment of this sodium channel protein. The observation of a distinct mutation that cosegregates with HYPP in two families and appears as a de novo mutation in a third establishes SCN4A as the HYPP gene. Furthermore, this mutation is associated with a form of HYPP in which fixed muscle weakness is seen.