Familial Hemiplegic Migraine and Episodic Ataxia Type-2 Are Caused by Mutations in the Ca2+Channel Gene CACNL1A4

MGC-Department of Human Genetics, Sylvius Laboratory, Leiden University, The Netherlands.
Cell (Impact Factor: 32.24). 12/1996; 87(3):543-52.
Source: PubMed


Genes for familial hemiplegic migraine (FHM) and episodic ataxia type-2 (EA-2) have been mapped to chromosome 19p13. We characterized a brain-specific P/Q-type Ca2+ channel alpha1-subunit gene, CACNL1A4, covering 300 kb with 47 exons. Sequencing of all exons and their surroundings revealed polymorphic variations, including a (CA)n-repeat (D19S1150), a (CAG)n-repeat in the 3'-UTR, and different types of deleterious mutations in FHM and EA-2. In FHM, we found four different missense mutations in conserved functional domains. One mutation has occurred on two different haplotypes in unrelated FHM families. In EA-2, we found two mutations disrupting the reading frame. Thus, FHM and EA-2 can be considered as allelic channelopathies. A similar etiology may be involved in common types of migraine.

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    • "The S218L variant exhibits larger gain-of-function (in vitro) and higher SD susceptibility (in vivo) in comparison to the R192Q mutation (33, 34). In contrast to pure hemiplegic migraine associated with the R192Q mutation, attacks in patients carrying the S218L mutation are sometimes accompanied by disturbances of consciousness, such as coma or stupor, and generalized seizures (18). "
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    ABSTRACT: Objective Familial hemiplegic migraine (FHM) is an autosomal dominantly inherited subtype of migraine with aura, characterized by transient neurological signs and symptoms. Typical hemiplegic migraine attacks start in the first or second decade of life. Some patients with FHM suffer from daily recurrent attacks since childhood. Results from extensive studies of cellular and animal models have indicated that gene mutations in FHM increase neuronal excitability and reduce the threshold for spreading depression (SD). SD is a transient wave of profound neuronal and glial depolarization that slowly propagates throughout the brain tissue and is characterized by a high amplitude negative DC shift. After induction of SD, S218L mutant mice exhibited neurological signs highly reminiscent of clinical attacks in FHM type 1 patients carrying this mutation. FHM1 with ataxia is attributable to specific mutations that differ from mutations that cause pure FHM1 and have peculiar consequences on cerebellar Cav2.1 currents that lead to profound Purkinje cell dysfunction and neuronal loss with atrophy. SD in juvenile rats produced neuronal injury and death. Hormonal factors involved in FHM affect SD initiation and propagation. The data identify SD as a possible target of treatment of FHM. In addition, FHM is a useful model to explore the mechanisms of more common types of migraine.
    Full-text · Article · Mar 2014 · Iranian Journal of Child Neurology
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    • "Two CaV2.1 channelopathies—familial hemiplegic migraine type 1 (FHM1) and episodic ataxia type 2 (EA2)—result from mutations (gain- and loss-of-function, respectively) in human CACNA1A, which encodes the α1 subunit of presynaptic CaV2.1-type calcium channels (Ophoff et al., 1996; Pietrobon, 2010a). A third disorder—spinocerebellar ataxia type 6 (SCA6)—results from poly-glutamine (polyQ) expansion in the CACNA1A gene product (Zhuchenko et al., 1997). "
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    ABSTRACT: Throughout life, animals face a variety of challenges such as developmental growth, the presence of toxins, or changes in temperature. Neuronal circuits and synapses respond to challenges by executing an array of neuroplasticity paradigms. Some paradigms allow neurons to up- or downregulate activity outputs, while countervailing ones ensure that outputs remain within appropriate physiological ranges. A growing body of evidence suggests that homeostatic synaptic plasticity (HSP) is critical in the latter case. Voltage-gated calcium channels gate forms of HSP. Presynaptically, the aggregate data show that when synapse activity is weakened, homeostatic signaling systems can act to correct impairments, in part by increasing calcium influx through presynaptic CaV2-type channels. Increased calcium influx is often accompanied by parallel increases in the size of active zones and the size of the readily releasable pool of presynaptic vesicles. These changes coincide with homeostatic enhancements of neurotransmitter release. Postsynaptically, there is a great deal of evidence that reduced network activity and loss of calcium influx through CaV1-type calcium channels also results in adaptive homeostatic signaling. Some adaptations drive presynaptic enhancements of vesicle pool size and turnover rate via retrograde signaling, as well as de novo insertion of postsynaptic neurotransmitter receptors. Enhanced calcium influx through CaV1 after network activation or single cell stimulation can elicit the opposite response-homeostatic depression via removal of excitatory receptors. There exist intriguing links between HSP and calcium channelopathies-such as forms of epilepsy, migraine, ataxia, and myasthenia. The episodic nature of some of these disorders suggests alternating periods of stable and unstable function. Uncovering information about how calcium channels are regulated in the context of HSP could be relevant toward understanding these and other disorders.
    Full-text · Article · Feb 2014 · Frontiers in Cellular Neuroscience
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    • "To different extent, dystonia, ataxia, premature death, and epilepsy have also been observed and extensively studied in natural Cacna1a gene mouse mutants leaner, tottering, rolling Nagoya and rocker [14], [15]. In humans, Cacna1a gene mutations are associated with familial hemiplegic migraine type 1, episodic ataxia type 2 and spinocerebellar ataxia type 6 [16]–[18]. "
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    ABSTRACT: Voltage-gated CaV2.1 (P/Q-type) Ca(2+) channels located at the presynaptic membrane are known to control a multitude of Ca(2+)-dependent cellular processes such as neurotransmitter release and synaptic plasticity. Our knowledge about their contributions to complex cognitive functions, however, is restricted by the limited adequacy of existing transgenic CaV2.1 mouse models. Global CaV2.1 knock-out mice lacking the α1 subunit Cacna1a gene product exhibit early postnatal lethality which makes them unsuitable to analyse the relevance of CaV2.1 Ca(2+) channels for complex behaviour in adult mice. Consequently we established a forebrain specific CaV2.1 knock-out model by crossing mice with a floxed Cacna1a gene with mice expressing Cre-recombinase under the control of the NEX promoter. This novel mouse model enabled us to investigate the contribution of CaV2.1 to complex cognitive functions, particularly learning and memory. Electrophysiological analysis allowed us to test the specificity of our conditional knock-out model and revealed an impaired synaptic transmission at hippocampal glutamatergic synapses. At the behavioural level, the forebrain-specific CaV2.1 knock-out resulted in deficits in spatial learning and reference memory, reduced recognition memory, increased exploratory behaviour and a strong attenuation of circadian rhythmicity. In summary, we present a novel conditional CaV2.1 knock-out model that is most suitable for analysing the in vivo functions of CaV2.1 in the adult murine forebrain.
    Full-text · Article · Dec 2013 · PLoS ONE
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