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  • 1
    Electronic Resource
    Electronic Resource
    Enhanced inactivation and acceleration of activation of the sodium channel associated with epilepsy in man (2001)
    Oxford, UK : Blackwell Science Ltd
    European journal of neuroscience 13 (2001), S. 0 
    Details
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Generalized epilepsy with febrile seizures-plus (GEFS+) is a benign Mendelian syndrome characterized by childhood-onset febrile and afebrile seizures. Three point mutations within two voltage-gated sodium channel genes have been identified so far: in GEFS+ type 1 a mutation in the β1-subunit gene SCN1B, and in GEFS+ type 2 two mutations within the neuronal α-subunit gene SCN1A. Functional expression of the SCN1B and one of the SCN1A mutations revealed defects in fast channel inactivation which are in line with previous findings on myotonia causing mutations in SCN4A, the skeletal muscle sodium channel α-subunit gene, all showing an impaired fast inactivation. We now studied the second GEFS+ mutation (T875M in SCN1A), using the highly homologous SCN4A gene (mutation T685M). Unexpectedly, the experiments revealed a pronounced enhancement of both fast and slow inactivation and a defect of channel activation for T685M compared to wild-type channels. Steady-state fast and slow inactivation curves were shifted in the hyperpolarizing direction, entry into slow inactivation was threefold accelerated, recovery from slow inactivation was slowed by threefold and the time course of activation was slightly but significantly accelerated. In contrast to other disease-causing mutations in SCN1A, SCN1B and SCN4A, the only mechanism that could explain hyperexcitability of the cell membrane would be the acceleration of activation. Because the enhancement of slow inactivation was the most obvious alteration in gating found for T685M, this might be the disease-causing mechanism for that mutation. In this case, the occurrence of epileptic seizures could be explained by a decrease of excitability of inhibitory neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.0953-816x.2001.01590.x
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  • 2
    Electronic Resource
    Electronic Resource
    Expression in mammalian cells and electrophysiological characterization of two mutant Kv1.1 channels causing episodic ataxia type 1 (EA-1) (1999)
    Oxford, UK : Blackwell Science Ltd
    European journal of neuroscience 11 (1999), S. 0 
    Details
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Episodic ataxia type 1 (EA-1) is a rare neurological disorder and was the first ionic channel disease to be associated with defects in a potassium channel. Until now 10 different point mutations in the KCNA1-gene have been reported to cause this disorder. We have investigated the functional consequences of two mutations leading to amino acid substitutions in the first and sixth transmembrane segments of a Kv1.1 channel subunit, by means of the patch-clamp technique; we injected cRNA coding for, respectively, F184C and V408A mutant Kv1.1 channels into mammalian cells and compared the resulting currents with those in the wild-type. The expression levels of F184C and V408A mutant channels relative to that of the wild-type was 38 and 68%, respectively. Since the single-channel conductance of the F184C mutant was similar to that of the wild-type (12 pS) without an apparent change in the maximum open probability, we conclude that the lower expression level in the F184C mutant channels is due to a reduced number of functional channels on the cell surface. F184C activated slower, and at more depolarized potentials, and deactivated faster compared with the wild-type. V408A channels deactivated and inactivated faster compared with the wild-type. Studies with different extracellular cations and tetraethylammonium gave no indication that the pore structure was changed in the mutant channels. Acetazolamide, that is helpful in some patients suffering from EA-1, was without effect on Kv1.1 wild-type or mutant channels. This study confirms and extends earlier studies on the functional consequences of Kv1.1 mutations associated with EA-1, in an attempt to understand the pathophysiology of the disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1460-9568.1999.00659.x
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  • 3
    Electronic Resource
    Electronic Resource
    Fura-2 detected myoplasmic calcium and its correlation with contracture force in skeletal muscle from normal and malignant hyperthermia susceptible pigs (1988)
    Springer
    Pflügers Archiv 411 (1988), S. 648-653 
    Details
    ISSN: 1432-2013
    Keywords: Intercostal muscle fibers ; Resting [Ca2+] ; Halothane ; Caffeine ; Fluorescence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Fura-2 was used to estimate myoplasmic [Ca2+] in intact intercostal muscle fibers from normal and malignant hyperthermia susceptible (MHS) pigs. Small muscle bundles (20–50 fibers) were loaded with the membrane-permeant form of the dye. Resting myoplasmic [Ca2+] were not significantly different in normal and MHS muscles. Halothane produced increases in myoplasmic Ca2+ with associated contractures in MHS muscles, but not in normal muscles. These halothane effects were reversible. Caffeine produced increases in myoplasmic Ca2+ and contractures in both MHS and normal muscles. The threshold concentrations were lower in the MHS muscles. The correlations between myoplasmic [Ca2+] and force in MHS and normal muscles were similar.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00580861
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  • 4
    Electronic Resource
    Electronic Resource
    Localization of the malignant hyperthermia susceptibility locus to human chromosome 19ql2–13.2 (1990)
    [s.l.] : Nature Publishing Group
    Nature 343 (1990), S. 562-564 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] FIG. 1 Linkage map of 14 markers on chromosome 19q. Data are from a multipoint analysis of the CEPH pedigrees19 with the location of GPI from somatic cell hybrid data18 and the position of the DM locus distal to CKMM from analysis of recombinant family members26"28. A standardized test (based ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/343562a0
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  • 5
    Electronic Resource
    Electronic Resource
    On identification of Na+ channel gating schemes using moving-average filtered hidden Markov models (1999)
    Springer
    European biophysics journal 28 (1999), S. 605-609 
    Details
    ISSN: 1432-1017
    Keywords: Key words Single channel recording ; Sodium channel ; Gating scheme ; Hidden Markov model ; Anti-aliasing filter
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Physics
    Notes: Abstract  Transitions between distinct kinetic states of an ion channel are described by a Markov process. Hidden Markov models (HMM) have been successfully applied in the analysis of single ion channel recordings with a small signal-to-noise ratio. However, we have recently shown that the anti-aliasing low-pass filter misleads parameter estimation. Here, we show for the case of a Na+ channel recording that the standard HMM do neither allow parameter estimation nor a correct identification of the gating scheme. In particular, the number of closed and open states is determined incorrectly, whereas a modified HMM considering the anti-aliasing filter (moving-average filtered HMM) is able to reproduce the characteristic properties of the time series and to perform gating scheme identification.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002490050243
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  • 6
    Electronic Resource
    Electronic Resource
    Linkage data suggesting allelic heterogeneity for paramyotonia congenita and hyperkalemic periodic paralysis on chromosome 17 (1991)
    Springer
    Human genetics 〈Berlin〉 88 (1991), S. 71-74 
    Details
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Paramyotonia congenita (PC), an autosomal dominant non-progressive muscle disorder, is characterised by cold-induced stiffness followed by muscle weakness. The weakness is caused by a dysfunction of the sodium channel in muscle fibre. Parts of the gene coding for the α-subunit of the sodium channel of the adult human skeletal muscle (SCN4A) have been localised on chromosome 17. To investigate the role of this gene in the etiology of PC, a linkage analysis in 17 well-defined families was carried out. The results (z=20.61, Θ=0.001) show that the mutant gene responsible for the disorder is indeed tightly linked to the SCN4A gene. The mutation causing hyperkalemic periodic paralysis (HyperPP) with myotonia has previously been mapped to this gene locus by the same candidate gene approach. Thus, our data suggest that PC and HyperPP are caused by allelic mutations at a single locus on chromosome 17.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00204932
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  • 7
    Electronic Resource
    Electronic Resource
    Genetic heterogeneity in hypokalemic periodic paralysis (hypoPP) (1994)
    Springer
    Human genetics 〈Berlin〉 94 (1994), S. 551-556 
    Details
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant disorder belonging to a group of muscle diseases known to involve an abnormal function of ion channels. The latter includes hypokalemic and hyperkalemic periodic paralyses, and non-dystrophic myotonias. We recently showed genetic linkage of hypoPP to loci on chromosome 1q31-32, co-localized with the DHP-sensitive calcium channel CACNL1A3. We propose to term this locus hypoPP-1. Using extended haplotypes with new markers located on chromosome 1q31-32, we now report the detailed mapping of hypoPP-1 within a 7 cM interval. Two recombinants between hypoPP-1 and the flanking markers D1S413 and D1S510 should help to reduce further the hypoPP-1 interval. We used this new information to demonstrate that a large family of French origin displaying hypoPP is not genetically linked to hypoPP-1. We excluded genetic linkage over the entire hypoPP-1 interval showing for the first time genetic heterogeneity in hypoPP.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00211025
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  • 8
    Electronic Resource
    Electronic Resource
    Recessive Schwartz-Jampel syndrome (SJS): confirmation of linkage to chromosome 1p, evidence of genetic homogeneity and reduction of the SJS locus to a 3-cM interval (1996)
    Springer
    Human genetics 〈Berlin〉 98 (1996), S. 380-385 
    Details
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Schwartz-Jampel syndrome (SJS), or chondrodystrophic myotonia, is a rare autosomal recessive disorder characterized by generalized myotonia resulting in a particular, recognizable facies and osteoarticular abnormalities. Some of us have recently shown genetic linkage of SJS to a locus on 1p34–p36.1 in five families. Here, we show by homozygosity mapping and segregation analysis that eight new families are most likely linked to the SJS locus on chromosome 1, confirming the localization of SJS to chromosome 1p and suggesting genetic homogeneity. Recombination events reduced the SJS locus from a genetic interval of 8 to 3 cM, which should facilitate the identification of the SJS gene. Low clinical variability was observed between the studied families, except for osteoarticular abnormalities. Since the severity and the location of osteoarticular abnormalities varied from one individual to another, even in the same families, other factors than the SJS gene itself, genetic or epigenetic, might contribute to the phenotype.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004390050225
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  • 9
    Electronic Resource
    Electronic Resource
    Effects of temperature and mexiletine on the F1473S Na+ channel mutation causing paramyotonia congenita (1998)
    Springer
    Pflügers Archiv 436 (1998), S. 757-765 
    Details
    ISSN: 1432-2013
    Keywords: Key words Human skeletal muscle ; Inactivation ; Ion channel ; Local anaesthetic ; Myotonia ; Patch-clamp ; Pharmacology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The F1473S mutation of the adult human skeletal muscle Na+ channel causes paramyotonia congenita, a disease characterized by muscle stiffness sometimes followed by weakness in a cold environment. The symptoms are relieved by the local anaesthetic mexiletine. This mutation, which resides in the cytoplasmic S4-S5 loop in domain IV of the α-subunit, was studied by heterologous expression in HEK293 cells using standard patch-clamp techniques. Compared to wild-type (WT) channels, those with the F1473S mutation exhibit a twofold slowing of fast inactivation, an increased persistent Na+ current, a +18-mV shift in steady-state inactivation and a fivefold acceleration of recovery from fast inactivation; slow inactivation was similar for both clones. Single-channel recordings for the F1473S mutation revealed a prolonged mean open time and an increased number of channel reopenings that increased further upon cooling. The pharmacological effects of mexiletine on cells expressing either WT, F1473S or G1306E channels were studied. G1306E is a myotonia-causing mutation located within the inactivation gate that displays similar but stronger inactivation defects than F1473S. The hyperpolarizing shift in steady-state inactivation induced by mexiletine was almost identical for all three clones. In contrast, this agent had a reduced effectiveness on the phasic (use-dependent) block of Na+ currents recorded from the mutants: the relative order of block was WT〉F1473S〉G1306E. We suggest that the relative effectiveness of mexiletine is associated with the degree of abnormal channel inactivation and that the relative binding affinity of mexiletine is not substantially different between the mutations or the WT.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004240050699
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