Functional consequences of a domain 1/S6 segment sodium channel mutation associated with painful congenital myotonia. (1/78)

An unusual form of painful congenital myotonia is associated with a novel SCN4A mutation causing a valine to methionine substitution in the domain 1/S6 segment of the skeletal muscle sodium channel. We studied the functional characteristics of this mutant allele using a recombinant channel to gain understanding about the nature of the biophysical defect responsible for this unique phenotype. When expressed heterologously in a cultured mammalian cell line (tsA201), the mutant channel exhibits subtle defects in its gating properties similar, but not identical, to other myotonia-producing sodium channel mutations. The main abnormalities are the presence of a small non-inactivating current that occurs during short test depolarizations, a shift in the voltage-dependence of channel activation to more negative potentials, and a slowing of the time course of recovery from inactivation. Flecainide, a potent sodium channel blocker previously reported to benefit patients affected by this form of myotonia, effectively inhibits the abnormal sodium current associated with expression of the mutant channel. Our findings demonstrate the unique pattern of sodium channel dysfunction associated with a D1/S6 myotonia-producing sodium channel mutation, and provide a mechanism for the beneficial effects of flecainide in this setting.  (+info)

Left ventricular diastolic function in congenital myotonic dystrophy. (2/78)

OBJECTIVE: Examination of left ventricular function and conduction abnormalities in myotonic dystrophy. DESIGN: Twelve patients (median age, 13.7 years) with myotonic dystrophy had detailed electrocardiography and echocardiography performed. Echocardiographic parameters were compared with body surface area (BSA) matched median normal values. RESULTS: Fractional shortening was slightly reduced (by 28-29%) in three patients and three patients had mild mitral valve prolapse. Diastolic function was abnormal; isovolumic relaxation time (IVRT) and duration of early filling were prolonged compared with control values (median IVRT, 74 v 61 ms). Peak E velocity was increased (median, 0.82 v 0.78 m/s) but atrial phase filling was normal. Heart rate was reduced (median, 68 v 81 beats/min). Conduction abnormalities were common but showed no clear relations with diastolic abnormalities. CONCLUSIONS: Young patients with myotonic dystrophy have myocardial diastolic dysfunction as well as abnormal electrophysiology. The prognostic implications of such abnormalities require further study.  (+info)

Mutant channels contribute <50% to Na+ current in paramyotonia congenita muscle. (3/78)

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.  (+info)

Characterization of a new sodium channel mutation at arginine 1448 associated with moderate Paramyotonia congenita in humans. (4/78)

1. Paramyotonia congenita is a temperature-sensitive skeletal muscle disorder caused by missense mutations that occur in the adult skeletal muscle voltage-gated sodium channel. We report here the identification of a new genetic mutation in a family with the paramyotonia congenita phenotype. 2. Single-strand conformation polymorphism analysis and DNA sequencing showed that the defect was linked to a single nucleotide substitution causing an amino acid change from an arginine to a serine at position 1448 in the human sodium channel alpha-subunit. 3. Expression of the altered protein in human embryonic kidney (HEK) 293 cells revealed several defects in channel function: (i) the rate of fast inactivation was slower in the mutant channel compared with wild-type, (ii) steady-state fast inactivation was shifted towards hyperpolarizing potentials, (iii) the R1448S channels deactivated much more slowly, and (iv) the mutant channels recovered from the fast inactivated state more rapidly. 4. By contrast, the activation curve, steady-state slow inactivation and the rate of onset and recovery from slow inactivation were not altered by the R1448S mutation. 5. These 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.  (+info)

A missense mutation in canine C1C-1 causes recessive myotonia congenita in the dog. (5/78)

Myotonia congenita is an inherited disorder of sarcolemmal excitation leading to delayed relaxation of skeletal muscle following contractions. Mutations in a skeletal muscle voltage-dependent chloride channel, CIC-1, have been identified as the molecular genetic basis for the syndrome in humans, and in two well characterized animal models of the disease: the myotonic goat, and the arrested development of righting (adr) mouse. We now report the molecular genetic and electrophysiological characterization of a canine CIC-1 mutation that causes autosomal recessive myotonia congenita in miniature Schnauzers. The mutation results in replacement of a threonine residue in the D5 transmembrane segment with methionine. Functional characterization of the mutation introduced into a recombinant CIC-1 and heterologously expressed in a cultured mammalian cell line demonstrates a profound effect on the voltage-dependence of activation such that mutant channels have a greatly reduced open probability at voltages near the resting membrane potential of skeletal muscle. The degree of this dysfunction is greatly diminished when heterodimeric channels containing a wild-type and mutant subunit are expressed together as a covalent concatemer strongly supporting the observed recessive inheritance in affected dog pedigrees. Genetic and electrophysiological characterization of the myotonic dog provides a new and potentially valuable animal model of an inherited skeletal muscle disease that has advantages over existing models of myotonia congenita.  (+info)

Effects of temperature on slow and fast inactivation of rat skeletal muscle Na(+) channels. (6/78)

Patch-clamp studies of mammalian skeletal muscle Na(+) channels are commonly done at subphysiological temperatures, usually room temperature. However, at subphysiological temperatures, most Na(+) channels are inactivated at the cell resting potential. This study examined the effects of temperature on fast and slow inactivation of Na(+) channels to determine if temperature changed the fraction of Na(+) channels that were excitable at resting potential. The loose patch voltage clamp recorded Na(+) currents (I(Na)) in vitro at 19, 25, 31, and 37 degrees C from the sarcolemma of rat type IIb fast-twitch omohyoid skeletal muscle fibers. Temperature affected the fraction of Na(+) channels that were excitable at the resting potential. At 19 degrees C, only 30% of channels were excitable at the resting potential. In contrast, at 37 degrees C, 93% of Na(+) channels were excitable at the resting potential. Temperature did not alter the resting potential or the voltage dependencies of activation or fast inactivation. I(Na) available at the resting potential increased with temperature because the steady-state voltage dependence of slow inactivation shifted in a depolarizing direction with increasing temperature. The membrane potential at which half of the Na(+) channels were in the slow inactivated state was shifted by +16 mV at 37 degrees C compared with 19 degrees C. Consequently, the low availability of excitable Na(+) channels at subphysiological temperatures resulted from channels being in the slow, inactivated state at the resting potential.  (+info)

Mechanism of inverted activation of ClC-1 channels caused by a novel myotonia congenita mutation. (7/78)

The voltage-gated chloride channel ClC-1 is the major contributor of membrane conductance in skeletal muscle and has been associated with the inherited muscular disorder myotonia congenita. Here, we report a novel mutation identified in a recessive myotonia congenita family. This mutation, Gly-499 to Arg (G499R) is located in the putative transmembrane domain 10 of the ClC-1 protein. In contrast to normal ClC-1 channels that deactivate upon hyperpolarization, functional expression of G499R ClC-1 yielded a hyperpolarization-activated chloride current when measured in the presence of a high (134 mM) intracellular chloride concentration. Current was abolished when measured with a physiological chloride transmembrane gradient. Electrophysiological analysis of other Gly-499 mutants (G499K, G499Q, and G499E) suggests that the positive charge introduced by the G499R mutation may be responsible for this unique gating behavior. To further explore the function of domain 10, we mutated two charged residues near Gly-499 of ClC-1. Functional analyses of R496Q, R496Q/G499R, R496K, and E500Q mutant channels suggest that the charged residues in domain 10 are important for normal channel function. Study of these mutants may shed further light on the structure and voltage-gating of this channel.  (+info)

Propagation disturbance of motor unit action potentials during transient paresis in generalized myotonia: a high-density surface EMG study. (8/78)

Patients with autosomal recessive generalized myotonia, or Becker's disease, often suffer from a peculiar transient paresis. As yet, the relationship between this transient paresis and the defect in the gene encoding for a voltage gated Cl- channel protein in the muscle membrane of these patients is unclear. In order to gain a better understanding of the electrophysiological properties of the muscle fibre membrane in these generalized myotonia patients, we have studied transient paresis with a novel high-density surface EMG (sEMG) technique. We conclude that the transient paresis is explained by a deteriorating muscle membrane function, ending in conduction block and paresis. Multi-channel sEMG during the period of force decline in transient paresis shows a decrease in peak-peak amplitude of the motor unit action potentials from endplate towards tendon. This disturbance increases with time and place, indicating a deteriorating membrane function, and ends in a complete blocking of propagation within seconds. Spatiotemporally, this leads to a V-shaped sEMG pattern. In a more general sense, this contribution shows how spatiotemporal information, available through non-invasive high-density sEMG, may provide novel insights into electrophysiological aspects of membrane dysfunction.  (+info)

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