Coding and Noncoding Variation of the Human Calcium-Channel β4-Subunit Gene CACNB4 in Patients with Idiopathic Generalized Epilepsy and Episodic Ataxia

Humboldt-Universität zu Berlin, Berlín, Berlin, Germany
The American Journal of Human Genetics (Impact Factor: 10.93). 06/2000; 66(5):1531-9. DOI: 10.1086/302909
Source: PubMed


Inactivation of the beta4 subunit of the calcium channel in the mouse neurological mutant lethargic results in a complex neurological disorder that includes absence epilepsy and ataxia. To determine the role of the calcium-channel beta4-subunit gene CACNB4 on chromosome 2q22-23 in related human disorders, we screened for mutations in small pedigrees with familial epilepsy and ataxia. The premature-termination mutation R482X was identified in a patient with juvenile myoclonic epilepsy. The R482X protein lacks the 38 C-terminal amino acids containing part of an interaction domain for the alpha1 subunit. The missense mutation C104F was identified both in a German family with generalized epilepsy and praxis-induced seizures and in a French Canadian family with episodic ataxia. These coding mutations were not detected in 255 unaffected control individuals (510 chromosomes), and they may be considered candidate disease mutations. The results of functional tests of the truncated protein R482X in Xenopus laevis oocytes demonstrated a small decrease in the fast time constant for inactivation of the cotransfected alpha1 subunit. Further studies will be required to evaluate the in vivo consequences of these mutations. We also describe eight noncoding single-nucleotide substitutions, two of which are present at polymorphic frequency, and a previously unrecognized first intron of CACNB4 that interrupts exon 1 at codon 21.

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Available from: Michel De Waard
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    • "Mice homozygous for the mutation are first recognized at day 15 by their lethargic behavior with gait instability (ataxia) and occasional seizures, which resemble human petit mal seizures. Because a mutation in the human Cacnb4 gene causes a juvenile form of epilepsy, lethargic mice are frequently considered as a model for idiopathic epilepsy (Escayg et al. 2000). "
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    ABSTRACT: We have generated a novel, neuro-specific ncRNA microarray, covering 1472 ncRNA species, to investigate their expression in different mouse models for central nervous system diseases. Thereby, we analyzed ncRNA expression in two mouse models with impaired calcium channel activity, implicated in Epilepsy or Parkinson's disease, respectively, as well as in a mouse model mimicking pathophysiological aspects of Alzheimer's disease. We identified well over a hundred differentially expressed ncRNAs, either from known classes of ncRNAs, such as miRNAs or snoRNAs or which represented entirely novel ncRNA species. Several differentially expressed ncRNAs in the calcium channel mouse models were assigned as miRNAs and target genes involved in calcium signaling, thus suggesting feedback regulation of miRNAs by calcium signaling. In the Alzheimer mouse model, we identified two snoRNAs, whose expression was deregulated prior to amyloid plaque formation. Interestingly, the presence of snoRNAs could be detected in cerebral spine fluid samples in humans, thus potentially serving as early diagnostic markers for Alzheimer's disease. In addition to known ncRNAs species, we also identified 63 differentially expressed, entirely novel ncRNA candidates, located in intronic or intergenic regions of the mouse genome, genomic locations, which previously have been shown to harbor the majority of functional ncRNAs.
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    • "Until now, there have been at least seven distinct subtypes of episodic ataxias based on clinical features and genetics. Mutations of four genes have been linked to different syndromes: KCNA1, CACNA1A, CACNB4, and SLCIA3 for EA1, EA2, EA5 and EA6 respectively [2], [3], [4], [5]. "
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    ABSTRACT: Type 2 episodic ataxia (EA2) is the most common subtype among a group of rare hereditary syndromes characterized by recurrent attacks of ataxia. More than 60 mutations and several gene rearrangements due to large deletions in CACNA1A gene have been reported so far for the cause of EA2. Because CACNA1A gene is a large gene containing 47 exons and there is no hot spot mutation, direct sequencing will be a challenge in clinical genetic testing. In this study, we used next generation sequencing technology to identify a novel nonsense mutation of CACNA1A (p.Tyr1957Ter, NP_001120693.1) resulting in truncated protein without 305 amino acids in the c-terminus. Sanger sequencing confirmed the heterozygous mutation of CACNA1A in a Chinese family with 11 affected individuals. Affected individuals experienced recurrent attacks with or without nystagmus, dysarthria, seizure, myokymia, dystonia, weakness, blurred vision, visual field defects, diplopia, migraine, dizziness, nausea and vomiting, sweating and abdominal pain. This is the first report of EA2 in a Chinese family that carries a novel mutation in CACNA1A gene and had abdominal pain as a novel phenotype associated with EA2.
    Full-text · Article · Feb 2013 · PLoS ONE
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    • "Elucidation of the underlying molecular defect in epileptic disorders brought the understanding that the neuronal membrane epileptogenicity is related either to disorders of synaptic transmission or to ionic channel dysfunction (Singh et al., 1998; Escayg et al., 2000; Hirose et al., 2002; Mulley et al., 2003). The underlying molecular mechanism of several electroclinical syndromes with onset in early life has been identified including Dravet syndrome (SCN1A and GABRG2 genes), Ohtahara syndrome (STXBP1, ARX, PLCb1) and West syndrome (PLCb1), as well as EIEE1 (PLCb1), EIEE2 (CDKL5), EIEE4 (STXBP1), and EIEE5 (SPTAN1) (Mari et al., 2005; Kurian et al., 2010; Saitsu et al., 2010; Carranza Rojo et al., 2011; Milh et al., 2011; Mastrangelo & Leuzzi, 2012). "

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