Hypokalemic periodic paralysis: an autosomal dominant muscle disorder caused by mutations in a voltage-gated calcium channel

Neuromuscular Disorders 7 (1997) 234–240

Hypokalemic periodic paralysis: an autosomal dominant muscle disorder caused by mutations in a voltage-gated calcium channel Pascale Lapie a, Philippe Lory b, Bertrand Fontaine a , c ,* a

INSERM CJF96108, Hoˆpital de la Salpeˆtrie`re, 47 boulevard de l’Hoˆpital, 75013 Paris, France CRBM, CNRS UPR 9008 and INSERM U249, BP 5051, 1919 route de Mende, 34033 Montpellier Cedex, France c Fe´de´ration de Neurologie, Hoˆpital de la Salpeˆtrie`re, 47 boulevard de l’Hoˆpital, 75013 Paris, France

b

in revised form 12 December 1996; accepted 14 January 1997 Received 27 September 1996; received revised version received

Abstract Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant disorder characterized by acute attacks of muscle weakness concomitant to a drop in blood potassium levels. Recent molecular work has shown that hypoPP is due to mutations in a skeletal muscle voltage-gated calcium channel: the dihydropyridine receptor (DHP receptor). Mutations affect segments S4 of domains II and IV, changing an arginine in position 528 and 1239 into an histidine, or an histidine or a glycine respectively. Surprisingly, expressing in vitro mutants channels in a non-muscular environnement resulted in functional calcium channels with minor modifications in electrophysiological properties. Expressing mutant channels in a muscular environnement or transgenic mice might help to bridge the gap between the knowledge of the molecular defect and the understanding of the pathophysiology of the disease.  1997 Elsevier Science B.V. Keywords: Hypokalemic periodic paralysis; Calcium channel; DHP receptor; Electrophysiological recordings; In vitro cell expression system

1. Introduction Periodic paralyses constitute a group of human hereditary muscle disorders characterized by acute and reversible attacks of muscle weakness. Based on the variations of blood potassium levels during attacks, periodic paralyses were classified into hypokalemic (hypoPP) and hyperkalemic periodic paralysis (hyperPP). The mode of inheritance of both disorders is autosomal dominant with a high penetrance. Periodic paralyses proved to be a paradigm for a candidate gene approach to neuromuscular diseases. Electrophysiological studies on muscle fibers of patients had shown abnormalities in the excitability of the sarcolemmal membrane suggesting a role for ion channels [1]. Linkage analysis and identification of mutations led to the discovery that hyperPP and hypoPP are caused by mutations in a sodium [2–13] and a calcium channel respectively [14– 16]. Sodium channel (SCN4A) amino-acid changes found in hyperPP patients have been extensively studied by in * Corresponding author.

0960-8966/97/$17.00  1997 Elsevier Science B.V. All rights reserved PII S0960- 8966 (97 )0 0435- 5

vitro expression systems (for review, see [17–19]) and provided both insights into the sodium channel functioning and into the pathophysiology of muscle paralysis. In this article, we will focus on hypoPP and on the most recent work on the expression of the mutated calcium channel.

2. Hypokalemic periodic paralysis (hypoPP) HypoPP is the most frequent form of periodic paralysis. The prevalence of hypoPP has been estimated at 1/100 000. HypoPP is characterized by episodic attacks of muscle weakness associated with a decrease in blood potassium levels. The onset of hypoPP is within the second decade of life and 60% of patients develop the disease before 16 years old [20]. Attacks of muscle weakness usually involve the four limbs. The frequency is variable from once during life-time to several per week. It generally decreases above the age of 30. Death due to paralysis of respiratory muscles [21] or from cardiac arrhythmia secondary to a severe drop in blood potassium levels has been reported, but must be

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considered as an exception [22]. The main provocatives factors in hypoPP are a carbohydrates rich meal and rest after exercise. Other provocative factors include emotion, stress, cold exposure and alcohol consumption. As a diagnostic test, glucose (2 g/kg) and insulin (0.1 U/kg) may be infused under a strict medical supervision. This results in an intake of potassium by muscle cells leading to hypokalemia and muscle paralysis. Treatment of attacks consists of the administration of potassium salts either oral ingestion or by i.v. injection depending on the severity of the drop in blood potassium levels. Preventive measures include avoiding the main provocative factors (ingestion of carbohydrate-rich meals and strenuous exercice). Acetazolamide as well as potassium salts have been proved to be useful in preventing attacks. In the fourth or fifth decade of life, a number of patients develop a permanent muscle weakness due to a vacuolar myopathy. The vacuolar myopathy occurs independently of the severity and the number of attacks [23]. Rare cases of children developing a vacuolar myopathy have also been reported [24]. Vacuolar myopathy is not specific to hypoPP and may be observed in hyperPP [25] and other muscular disorders [23]. A detailed morphological description of vacuole formation and evolution was given by Engel [26]. Vacuoles result from proliferation and degeneration of the sarcoplasmic reticulum and tubular system. The rupture of the vacuolar membrane allows fluid movements between the intra- and extra-cellular space and may consequently lead to muscle fiber destruction [26]. Other morphological features of hypoPP muscle fibers include tubular aggregates which originate from a massive proliferation of the sarcoplasmic reticulum [27], an increase in central nuclei, abnormal variation in fiber size, fiber necrosis and proliferation of connective tissue elements.

3. Mutations in a calcium channel: the dihydropyridine receptor Electrophysiological studies performed on muscle fibers of hypoPP patients maintained in vitro alive showed a mild depolarization of the sarcolemmal membrane exacerbated when decreasing the extra-cellular level of potassium [1]. This observation suggested a role for ion channels in the pathophysiology of hypoPP. Ion channels known to cause muscle diseases were tested by linkage analysis: the sodium channel (SCN4A) causing hyperPP and paramyotonia congenita as well as the chloride channel (CNCL1) implicated in myotonia congenita were eliminated as candidate genes [2,28,29]. In order to identify the hypoPP gene, a genomewide search was undertaken using highly polymorphic dinucleotide repeats [30] in three European families [14]. As a first step, candidate regions containing ion channel genes were selected. The hypoPP locus (named hypoPP-1) was assigned to chromosome 1q31–32 [14] in a region containing the calcium channel gene CACNL1A3 which encodes

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the a1-subunit of a skeletal muscle voltage-gated calcium channel termed the dihydropyridine receptor (DHP receptor) [31,32]. This voltage-gated calcium channel is composed of five subunits called a1, a2/d, b and g ([33] and for review, see [34]). The a1-subunit alone forms the ion-conducting pore, and contains the receptor for dihydropyridines and other ligands [35]. The other subunits regulate the function of the a1-subunit of the channel (for review, see [36–39]). Voltage-gated ion channels belong to a family sharing a similar structural organisation of the main a-subunits [34]. The a1-subunit is composed of four transmembrane domains (DI to IV) each of them containing six transmembrane a helices (S1 to S6) (Fig. 1). The DHP receptor is responsible for l-type calcium currents and is the voltagesensing element for excitation–contraction coupling (E–C coupling) in muscle [40]. The DHP receptor was tested as a candidate for the hypoPP gene defect. Three amino-acid substitutions were found in the coding region of the gene in hypoPP patients [15,16]. These changes replace a positively-charged arginine in position 528 in segment S4 of domain II by a weakly-positive histidine (R528H) and an arginine in position 1239 in the S4 segment of the fourth domain by either an histidine or a glycine (R1239H and R1239G) (Fig. 1). Segment S4 contains repetitions composed of a positivelycharged residue and two hydrophobic amino-acids. This repeated motive is thought to form an amphipathic helix exposing positively-charged residues within the membrane and thus confering to the channel its voltage-sensing properties ([41] and for review, see [42,43]). These amino-acid substitutions fulfilled all criteria of deletere mutations: (i) absence in a large number of controls [15,16], (ii) segregation with the hypoPP status in families from different ethnic origins [15,16,44–48], (iii) presence in a gene expressed in the affected tissue (skeletal muscle) [15,16,45], (iv) replacement of an highly conserved positively-charged residue (arginine) by a weakly-charged (histidine) or not charged (glycine) amino-acid within a functionally important part of the channel (the segment S4) and (v) occurence of a de novo R1239H substitution in two cases [16,47]. Searching for mutations in families from different ethnic backgrounds was possible using PCR amplification of genomic DNA followed by restriction-enzyme digestion [15,47]. Molecular studies performed in 16 Caucasian families demonstrated that R528H and R1239H are predominant mutations [47], whereas the R1239G mutation was only found in a single family [16]. By typing intragenic and flanking markers of the hypoPP-1 locus, no founder effect was found [46,47]. Accordingly, the observation of identical mutations in families of different ethnic backgrounds (Caucasian and Japanese) [47] and of de novo R1239H mutations [16,47] argue in favor of recurrent mutations within the CACLN1A3 gene. Finding only a small number of different mutations might be due to an observation bias: other mutations might be lethal or result in an unrelated phenotype.

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Fig. 1. Schematic diagram of the DHP receptor a1-subunit composed of four domains of internal homology (repeats DI to DIV) connected by intracellular loops. Each domain contains six hydrophobic segments (S1 to S6) forming putative transmembrane helices. Segments DIIS4 and DIVS4 containing a positively-charged amino-acid (arginine) at each third position are enlarged in inserts. Mutations R528H, R1239H and R1239G found in hypoPP patients are indicated. The R528H mutation substitutes the outermost arginine of the IIS4 segment [15] while the R1239H and R1239G mutations change a more internal arginine located within segment DIVS4 by either an histidine or a glycine [16].

This was reported for the sodium channel gene SCN4A which causes three distinct muscle disorders: hyperPP, PC and potassium aggravated myotonia (PAM) [2–13]. Polymorphisms resulting in conservative and nonconservative amino-acid substitutions also occur in the coding sequence of the CACLN1A3 gene [46]. Their potential role in modulating the hypoPP phenotype remains to be investigated. Although mutations in the DHP receptor are responsible for a majority of hypoPP cases, genetic heterogeneity was demonstrated in two families. One is of French origin [49] and the other of Portuguese ancestry. Localizing the gene using linkage analysis is underway. These new findings will probably broaden our knowledge on the molecular defects implicated in hypoPP and may point to partners interacting with the DHP receptor in vivo. Comparison of families with the R528H and the R1239H mutations revealed no clinical differences regarding the mean age of onset, the number of acute attacks, the precipitating factors and the proportion of patients presenting symptoms of vacuolar myopathy [47]. However, incomplete penetrance was only observed for women displaying the R528H mutation [47]. The reason for this variable penetrance is not known. One may speculate on a differential regulation of expression or function of the R528H mutated channel by sexual hormones. Such differential regulations

of ion channel activity by sexual hormones have already been described. Androgens indeed regulate voltage-dependent sodium currents in mouse muscle C2 cells [50]. Moreover, overexpression of the rat androgen receptor modifies the post-transcriptional processing of sodium channels leading to an absence of sodium currents [50]. Another example is the modulation of l-type Ca2 + channel activity by 17bestradiol in rat neostriatal neurons in a sex-specific manner [51]. This regulation acts via a G-protein-signaling pathway on the channel [51]. Hormones may act directly on the a1subunit or could indirectly modulate the activity of proteins interacting with the a1-subunit such as other subunits of the channel, the ryanodine receptor or proteins composing the cytoskeleton.

4. Expressing calcium channel mutations causing hypoPP In order to understand the pathophysiology of hypoPP, electrophysiological studies were performed in vitro on muscle fibers maintained alive and on different cell lines (Fig. 2). Calcium currents were recorded from myotubes obtained from muscle biopsies of hypoPP patients (Fig. 2A) and allowed the comparison of the electrophysiological

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Fig. 2. Electrophysiological studies on expressing calcium channel mutations in cellular systems. (A) Whole cell electrophysiological recordings were performed on myotubes from human satellite cells obtained after enzymatic dissociation of patient biopsies [44,45]. (B) Heterologous cellular expression systems were constructed by transfecting human embryonic kidney cell line (HEK 293) [54] or mouse L-cell line (Ltk-) [53] with an in vitro engineered vector expressing the mutated voltage-gated calcium channel. Whole cell patch clamp recordings were performed on selected transfected cells.

properties between the two main mutations R528H and R1239H of the DHP receptor [44,45]. HypoPP myotubes were shown to transcribe both normal and mutant genes [44,45]. Electrophysiological investigations of the R1239H mutation showed a marked reduction of the calcium current to 30% of the normal amplitude [44,45]. The steady-state inactivation curve was shifted to more negative potentials by 40 mV for the R528H mutation [44]. No activation defect was observed. To take into account these observations, a model of a loss of function mutation transmitted as a dominant trait was proposed [44,45]. The functional DHP receptor forms a tetrad composed of four monomers [52]. The presence of two R1239H mutated a1-subunits within a tetrad would inactivate the channel, and the remaining current would be due to wild type tetrads [45]. This model is also in accordance with the monophasic inactivation curve observed for the R528H mutant, postulating that one mutant subunit may modify the properties of the oligomer [44]. To explore the functional consequences of the R528H mutation, calcium channel heterologous cellular expression systems were developed (Fig. 2B) [53,54]. The first system used consisted in transfecting L-cells [53], a fibroblast-like mouse cell line which is totally devoided of any calcium channel subunits [35,55]. The R528H substitution was introduced by in vitro mutagenesis into the rabbit cDNA which shows 92% homology with its human counterpart [56–58]. Transfected L-cells with the R528H mutated cDNA produced a barium (an analogue of calcium which gives a

large current through L-type Ca2 + channels) current demonstrating that the mutation is not silent [53]. As the R528H mutation is located within segment S4, it was expected that the opening and closure of the channel might be disturbed. A similar mutation replacing the outermost arginine (R1448H) in the DIVS4 segment of the sodium channel (SCN4A) was found in patients with PC. When introduced into the sodium channel, this mutation slightly shifts (−5 mV) the steady-state channel inactivation [59]. Surprisingly, the kinetics and voltage-dependence of activation and inactivation were identical in the wild type and the mutated calcium channel in position 528 [53]. This apparent absence of effects in a segment thought to play a role in voltage-sensitivity of the channel adds a new and unexpected piece to the structure-relationships of the calcium channel. No difference was observed for the binding of ligands to the channel as tested by a dihydropyridine agonist, Bay K 8644, and an antagonist, PN 200-110 [53]. The only difference observed was a reduction by 3.2 fold of the barium current density. This modification might be either due to an alteration of the properties of the mutated channel or to an abnormal maturation or trafficking to the cell membrane of the mutated channel [53]. Taking into account this result, we may postulate that reducing the current density might contribute to muscle paralysis by lowering the intracellular calcium within the cell. Eventhough the ryanodine receptor (RYR receptor) is known to play a major role in the mobilisation of intracellular calcium stores during muscle contraction (for review see [60,61]) [62] a slow calcium

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influx through the DHP receptor might contribute to muscle contraction in a yet undetermined way. Lerche et al. [54] introduced an amino acid change equivalent to the R528H mutation (R650H) into the cardiac a1-subunit of the DHP receptor and expressed the channel in human embryonic kidney (HEK293) cells. The R528H cardiac mutation (R650H) produced a small (−5 mV) shift of both steady-state activation and inactivation [54]. Coexpressing the auxiliary a2/d-, cardiac b2-, and skeletal muscle specific b- and g-subunits did not result into significant differences between mutants and controls [54]. Heterologous in vitro expression systems have proved to be useful to investigate the kinetics of mutant channels. They have, however, not been able, till now, to proper understand the consequences of hypoPP mutations on the channel functioning. The complex structural organization of the DHP receptor composed of four1 monomers in muscles associated to the RYR receptor [52,63] contributes to enhance the function of the DHP receptor as a calcium channel [64]. Therefore, expression studies in a cell system closer to muscle fibers is required. Such experiments may bridge the gap between results obtained on hypoPP myotubes and on non muscle-cell lines. If the R528H and R1239H mutations indeed lead to a loss of function of the calcium channel, one may speculate that the entry of calcium within the muscle cell would be reduced, perturbing contraction, and resulting in paralysis. The loss of function hypothesis is not sufficient to explain old observations made on hypoPP muscle fibers maintained alive in vitro. Calcium fluxes through the DHP receptor have only a mild contribution to the resting membrane potential. In patients, sarcolemmal membranes showed a slightly depolarized resting membrane potential [1]. Lowering the extracellular potassium reinforced this phenomenom instead of hyperpolarizing the membrane as observed in controls [1]. Moreover, an increase in the conductance of sodium (GNa) not suppressed by tetrodotoxine (a specific sodium channel blocker) was hypothetized from electrophysiological recordings in patients’ fibers [1]. Furthermore, the loss of function model does not explain the observed drop of blood potassium levels during attacks.

5. Conclusion Recent advances in molecular genetics have demonstrated that a mutant voltage-gated calcium channel causes hypoPP [15,16]. The yet known mutations affect two arginines in position 528 and 1239 in segments S4 of domains II and IV. The mechanism of muscle paralysis in hypoPP is not yet understood. The DHP receptor has a dual function of a calcium channel and a voltage sensor in E–C coupling [40]. An impaired E–C coupling of the mutated DHP receptor might contribute to attacks of muscle weakness. Electrophysiological recordings on hypoPP myotubes and on mutant channels expressed in heterologous systems led,

apparently, to contradictory results. The complex sub-cellular organization of the DHP receptor in a muscle environnement might account for these discordant observations. Expressing mutants in muscle cells might help to bridge the gap. In addition to paralytic attacks, hypoPP patients also present a vacuolar myopathy. The DHP receptor is absent in the mouse mutant muscular dysgenesis (mdg) [65,66]. Evidence from studies of the mouse mutant indicate that the DHP receptor may play a role in the structural organization of the muscle fiber [67,68]. It is therefore conceivable that mutant channels might interfere with the structural organization of the reticulo-T-tubular system resulting in the formation of vacuoles and muscle fiber damage. This theory would not however explain why vacuolar myopathy is also observed in hyperPP in which mutated sodium channels are expressed in the sarcolemma. Thorough work on in vitro expression muscular models (cultured myotubes or adult muscle fibers) and transgenic mice might lead to the identification of factors which trigger and control vacuolar myopathy processes in hypoPP patients.

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