Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: CACNA1A
SNOMEDCT: 1260329005, 420932006, 715752006;
Cytogenetic location: 19p13.13 Genomic coordinates (GRCh38): 19:13,206,442-13,506,479 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.13 | Developmental and epileptic encephalopathy 42 | 617106 | Autosomal dominant | 3 |
| Episodic ataxia, type 2 | 108500 | Autosomal dominant | 3 | |
| Migraine, familial hemiplegic, 1 | 141500 | Autosomal dominant | 3 | |
| Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia | 141500 | Autosomal dominant | 3 | |
| Spinocerebellar ataxia 6 | 183086 | Autosomal dominant | 3 |
The CACNA1A gene encodes the transmembrane pore-forming subunit of the P/Q-type or CaV2.1 voltage-gated calcium channel (VGCC) (Kordasiewicz et al., 2006). Voltage-dependent Ca(2+) channels not only mediate the entry of Ca(2+) ions into excitable cells but are also involved in a variety of Ca(2+)-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Diriong et al. (1995) noted that calcium channels are multisubunit complexes and that the channel activity is directed by a pore-forming alpha-1 subunit, which is often sufficient to generate voltage-sensitive Ca(2+) channel activity. There are at least 6 classes of alpha-1 subunits: alpha-1A, B, C, D, E, and S, which are derived from 6 genes representing members of a gene family. The auxiliary subunits beta (e.g., 114207), alpha-2/delta, and gamma (e.g., 114209) regulate channel activity.
In addition to full-length CACNA1A, use of an internal ribosomal entry site in the CACNA1A transcript generates the CACNA1A C-terminal polypeptide, or alpha-1ACT, which functions as a transcription factor that mediates cerebellar development (Du et al., 2013).
Ophoff et al. (1996) characterized the CACNL1A4 gene and reported the amino acid sequence for residues 1 to 2262 of the protein. Northern analysis detected a 9.8-kb transcript in cerebellum, cerebral cortex, thalamus, and hypothalamus.
CACNA1A C-Terminal Polypeptide
Kordasiewicz et al. (2006) showed that a 75-kD human polypeptide consisting of the C terminus of CACNA1A is cleaved from the full-length protein and is present in the nucleus of HEK293 cells, as well as in mouse and human cerebellar Purkinje cells. Nuclear translocation depended partly on the presence of 3 nuclear localization signals within the C terminus.
Li et al. (2009) confirmed that C-terminal fragments of CACNA1A localized predominantly to the nucleus of HEK293 cells where they existed as speckle-like structures resembling promyelocytic leukemia nuclear bodies (PMLNBs).
Using mass spectrometric analysis, Du et al. (2013) determined that the 75-kD CACNA1A C-terminal polypeptide, which they called alpha-1ACT, began with the N-terminal sequence MIMEY at amino acid 1960 within the IQ-like domain of full-length CACNA1A. This N-terminal sequence did not overlap with any protease cleavage site, and expression of alpha-1ACT appeared to be due to use of a cryptic internal ribosomal entry site in the CACNA1A transcript.
Ophoff et al. (1996) found that the CACNA1A gene covers 300 kb and contains 47 exons. Sequencing of all exons and their surroundings revealed polymorphic variations, including a (CA)n-repeat (D19S1150) and a (CAG)n-repeat in the 3-prime-UTR.
Trettel et al. (2000) determined that the CACNL1A4 gene is alternatively spliced. A second isoform contains an alternative exon 37 that differs from the first by 97 nucleotides.
By FISH, Diriong et al. (1995) assigned the CACNA1A gene to chromosome 19p13.
Ca(2+) currents have been described on the basis of their biophysical and pharmacologic properties and include L-, N-, T-, P-, Q-, and R- types. The distinctive properties of these Ca(2+) channel types are related primarily to the expression of a variety of alpha-1 isoforms (Dunlap et al., 1995). The alpha-1A isoform is abundantly expressed in neuronal tissue and corresponds to the P/Q Ca(2+) channel type. The B and E isoforms are also expressed in neuronal tissue and correspond to the N-type and R-type of Ca(2+) channels, respectively (Lehmann-Horn and Jurkat-Rott, 1999). The genes encoding the alpha-1A, B, and E isoforms are symbolized CACNL1A4 or CACNA1A, CACNL1A5 (601012), and CACNL1A6 (601013) and are located on 19p13, 9q34 and 1q25-q31, respectively (Diriong et al., 1995). Alpha-1C, D, and S are involved with L-type Ca(2+) channels and are referred to as cardiac, neuroendocrine/brain, and skeletal muscle isoforms, respectively. They are encoded, respectively, by the CACNL1A1 gene (114205) on 12p13.3, the CACNL1A2 gene (114206) on 3p14.3, and the CACNL1A3 gene (114208) on 1q31-q32.
Takamori et al. (1997) and Takamori (2004) presented evidence suggesting that the alpha-1A subunit of the P/Q-type voltage-gated calcium channel contains antigenic sites implicated in Lambert-Eaton myasthenic syndrome.
Ackerman and Clapham (1997) provided a comprehensive review of the role of ion channel defects in disease. They provided useful illustrations of the physiology and structure of ion channels and of patch-clamp measurement of ion channel activity. They also discussed the design and use of drugs that target ion channels.
Using chromatin immunoprecipitation-sequencing and RNA-sequencing analyses, Du et al. (2019) identified dynamic changes in alpha-1Act-mediated gene regulation in rat PC12 pheochromocytoma cells. Many of the alpha-1Act-regulated genes were involved in neurogenesis, synaptic function, and cell adhesion. Quantitative RT-PCR analysis revealed that CACNA1A mRNA expression was maximal in human cerebellum from birth to 20 years of age and decreased gradually until reaching a plateau at age 50 years. A similar expression pattern was observed in cerebellum over the mouse life span. Du et al. (2019) presented evidence suggesting that bicistronic expression is common to multiple members of the VGCC family.
CACNA1A C-Terminal Polypeptide
Du et al. (2013) found that human alpha-1ACT bound an AT-rich enhancer element (TTATAA) in the 3-prime UTR of target genes, including BTG1 (109580), and increased expression of their reporter genes. Expression of alpha-1ACT in rat PC12 pheochromocytoma cells increased neurite outgrowth and expression of the predicted target gene.
Nishimune et al. (2004) showed that laminin beta-2 (LAMB2; 150325), a component of the synaptic cleft at the neuromuscular junction, binds directly to calcium channels that are required for neurotransmitter release from motor nerve terminals. This interaction leads to clustering of channels which in turn recruit other presynaptic components. Perturbation of this interaction in vivo results in disassembly of neurotransmitter release sites, resembling defects previously observed in an autoimmune neuromuscular disorder, Lambert-Eaton myasthenic syndrome (600003). Nishimune et al. (2004) concluded that their results identify an extracellular ligand of the voltage-gated calcium channel as well as a new laminin receptor, suggest a model for the development of nerve terminals, and provide clues to the pathogenesis of a synaptic disease.
Episodic Ataxia Type 2
In 2 unrelated patients with episodic ataxia type 2 (EA2; 108500), Ophoff et al. (1996) identified 2 mutations in the CACNA1A gene resulting in a disrupted reading frame. The first of these was deletion of a single C, nucleotide 4073 in codon 1266 (601011.0005), leading to a frameshift in the putative translation product with a stop codon in the next exon (codon 1294). See also 601011.0006.
Eunson et al. (2005) identified 2 splice site mutations in the CACNA1A gene in 2 unrelated families with EA2.
Riant et al. (2010) identified 4 different exonic deletions in the CACNA1A gene in 4 (14%) of 27 patients with episodic ataxia, in whom sequencing analysis was negative for CACNA1A point mutations. The EA2 phenotype in the patients with deletion was similar to that of patients with point mutations. The findings indicated that screening for deletions in the CACNA1A gene should also be done for a complete genetic workup.
Labrum et al. (2009) used multiplex ligation-dependent probe amplification (MLPA) to screen for large-scale genetic rearrangements in CACNA1A in 53 patients with a clinical diagnosis of episodic ataxia type 2 (EA2; 108500) or familial hemiplegic migraine type 1 (FHM1; 141500) in whom sequencing analysis was negative for CACNA1A point mutations. Labrum et al. (2009) identified 5 previously unreported large-scale deletions in the CACNA1A gene in 6 families with EA2 and the first pathogenic duplication in CACNA1A in an index patient with isolated episodic diplopia without ataxia (601011.0030) whose father reportedly had typical EA2 (601011.0030). Labrum et al. (2009) suggested that large-scale deletions and duplications can cause CACNA1A-associated channelopathies and that screening for large-scale rearrangements by rapid techniques such as MLPA should be considered as a first-line approach for genetic diagnostic testing of CACNA1A-associated channelopathies.
Familial Hemiplegic Migraine 1
In 5 unrelated families with familial hemiplegic migraine (FHM1; 141500), Ophoff et al. (1996) identified 4 different missense mutations in the CACNA1A gene (601011.0001-601011.0004). The authors raised the possibility that a similar defect may be involved in common types of migraine. Based on their mutational findings, Ophoff et al. (1996) suggested that FHM and EA2 are allelic channelopathies.
To determine the pathophysiologic consequences of missense mutations in the pore-forming human alpha-1A subunit of neuronal P/Q-type calcium channels associated with FHM, Kraus et al. (1998) introduced 4 single mutations (R192Q, 601011.0001; T666M, 601011.0002; V714A, 601011.0003; and I1811L, 601011.0004) into alpha-1A and investigated possible changes in channel function after functional expression of mutant subunits in Xenopus laevis oocytes. Changes in channel gating were observed for mutants T666M, V714A, and I1811L, but not for R192Q. Barium current inactivation was slightly faster in mutants T666M and V714A than in wildtype. The time course of recovery from channel inactivation was slower than in wildtype in T666M and accelerated in V714A and I1811L. Kraus et al. (1998) concluded that 3 of the 4 FHM mutations, located at the putative channel pore, alter inactivation gating and provide a pathophysiologic basis for the postulated neuronal instability in patients with FHM.
Kraus et al. (2000) continued their channel function studies with 3 additional mutations associated with FHM, including D715E (601011.0010) and V1457L (601011.0019). All 3 mutations significantly shifted the voltage dependence of activation to more negative potentials, resulting in altered calcium signaling by increasing channel activity at weak depolarizations. The authors suggested that these gating abnormalities underlie channel dysfunction in FHM.
Tottene et al. (2002) extended single-channel analysis to human voltage-gated P/Q type calcium channels (Ca(v)2.1) containing the V1457L mutation. This mutation increased the channel open probability by shifting its activation to more negative voltages and reduced both the unitary conductance and the density of functional channels in the membrane. To investigate the possibility of changes in Ca(v)2.1 function common to all FHM mutations, Tottene et al. (2002) calculated the product of single-channel current and open probability as a measure of calcium ion influx through single Ca(v)2.1 channels. All 5 FHM mutants analyzed showed a single-channel calcium ion influx larger than wildtype. They also expressed the FHM mutants in cerebellar granular cells from mice null for the mutation. The FHM mutations invariably led to a decrease of the maximal Ca(v)2.1 current density in neurons. The data showed that mutational changes of functional channel densities can be different in different cell types, and uncovered 2 functional effects common to all FHM mutations analyzed: increase of single-channel calcium ion influx and decrease of maximal Ca(v)2.1 current density in neurons. Tottene et al. (2002) hypothesized that these 2 apparently contradictory effects may underlie parallel processes of migraine and aura. This notion came from the clinical evidence that the migraine aura and the headache are not necessarily sequential, and that the aura may not be the trigger for the pain.
By studying mouse hippocampal neurons transfected with 4 human FHM1-related CACNA1A mutations (R192Q, T666M, V714A, and I1811L), Cao and Tsien (2005) observed that all 4 mutations resulted in decreased channel current without a change in voltage dependence. The mutant P/Q calcium channels were associated with a defect in GABA inhibitory transmission, although overall basal inhibitory transmission remained well preserved owing to a shift to N-type calcium channels. This shift increased the susceptibility to G protein-coupled modulation of presynaptic neurotransmission, which may be weakened in a heightened state of neuromodulation, like that provoked by triggers of migraine such as stress.
In approximately 20% of cases of FHM, the disease is associated with a mild permanent cerebellar ataxia which may be progressive (PCA). The CACNA1A gene is involved in about 50% of unselected hemiplegic migraine families and in all families with FHM/PCA. Ducros et al. (1999) screened 16 families and 3 nonfamilial cases with HPM/PCA for specific CACNA1A mutations and found 9 families and 1 nonfamilial case with the same T666M mutation (601011.0002), 1 novel mutation (D715E; 601011.0010) in 1 family, and no CAG repeat expansion. Both T666M and D715E substitutions were absent in 12 probands belonging to pure HPM families whose disease appeared to be linked to CACNA1A. Finally, haplotyping with neighboring markers suggested that T666M arose through recurrent mutational events. These data suggested that the PCA observed in 20% of HPM families results from specific pathophysiologic mechanisms.
Ducros et al. (2001) found 9 mutations in the CACNA1A gene in 15 of 16 probands of families affected by hemiplegic migraine and cerebellar signs, in 2 of 3 subjects with sporadic hemiplegic migraine and cerebellar signs, and in 4 of 12 probands of families affected by pure hemiplegic migraine. Genotyping of probands and relatives identified a total of 117 subjects with mutations whose clinical manifestations were assessed in detail. Of the subjects with mutations, 89% had attacks of hemiplegic migraine. One-third had severe attacks with coma, prolonged hemiplegia, or both, with full recovery. All 9 mutations, including 5 newly identified ones, were missense mutations. Six mutations were associated with hemiplegic migraine and cerebellar signs, and 83% of the subjects with these 6 mutations had nystagmus, ataxia, or both. Three mutations were associated with pure hemiplegic migraine.
Kim et al. (1998) sought mutations in the CACNA1A gene in 9 propositi of families with migraine headaches and episodic vertigo inherited in an autosomal dominant pattern. All 47 exons and flanking introns were subjected to SSCP analysis of PCR-amplified genomic DNA. Several polymorphisms were found, but no mutations were identified in any of the 47 exons of the 9 patients. They also determined the CAG repeat length at the 3-prime end of CACNA1A. No index case had a CAG repeat length greater than 13 (normal less than 17). Thus, mutations in CACNA1A must be uncommon in families with migraine headaches and episodic vertigo. Other ion channel genes expressed in the brain and inner ear remained candidate genes.
Labrum et al. (2009) used multiplex ligation-dependent probe amplification to screen for large-scale genetic rearrangements in CACNA1A in 53 patients with a clinical diagnosis of episodic ataxia type 2 or familial hemiplegic migraine type 1 in whom sequencing analysis was negative for CACNA1A point mutations. They identified a large-scale deletion in 1 patient with FHM1 (601011.0034) and in several patients with EA2.
Spinocerebellar Ataxia 6
Zhuchenko et al. (1997) identified expansion of a CAG repeat (601011.0007) predicted to code for polyglutamine in the C-terminal coding region of the CACNL1A4 gene in families with slowly progressive spinocerebellar ataxia designated SCA6 (183086).
Analysis of CAG repeat expansion in the CACNL1A4 gene by Ishikawa et al. (1997) revealed expansion in 8 of 15 Japanese families with autosomal dominant cerebellar ataxia; all affected individuals had larger alleles (range of CAG repeats 21 to 25), compared with alleles observed in neurologically normal Japanese (range 5 to 20 repeats). Inverse correlation between the CAG-repeat number and the age of onset was found in affected individuals with expansion. The number of CAG repeats in expanded chromosomes was completely stable within each family, which was consistent with the fact that anticipation was not statistically proved in these SCA6 families. Ishikawa et al. (1997) concluded that more than half of Japanese cases of ADPCA map to 19p and are strongly associated with the mild CAG expansion in the SCA6/CACNL1A4 gene.
Idiopathic Generalized Epilepsy
Chioza et al. (2001) provided direct evidence that the CACNA1A gene is involved in the etiology of idiopathic generalized epilepsy (IGE; 600669). They analyzed 4 single nucleotide polymorphisms (SNPs) from patients with IGE and found that 1 of them, SNP8, showed significant association with the disease. Because SNP8 is a silent polymorphism, the authors suggested that the association must be with a closely linked variant.
Developmental and Epileptic Encephalopathy 42
In 5 patients, including 2 sibs, with developmental and epileptic encephalopathy-42 (DEE42; 617106), the Epi4K Consortium (2016) identified 4 different heterozygous mutations in the CACNA1A gene (601011.0017, 601011.0035-601011.0037). The mutations were found by targeted sequencing of 27 candidate genes in 531 patients with a similar disorder. Functional studies of the variants and studies of patient cells were not performed.
Hoffman and Gardner (1997) pointed out that a drug designed to correct for the calcium-channel defect in patients with mutations of the CACNL1A4 gene may need to be completely 'phenotype-specific' as well as 'channel-specific' and may need to modulate the activity of the calcium channel differently between several disorders, despite the shared site of the biochemical defect. Conceivably, inhibitors of channel function may be effective in disorders caused by change-of-function mutations (e.g., in patients with hemiplegic migraine), whereas agents that stimulate the same channel might be beneficial in patients with loss-of-function mutations (such as those in episodic ataxia). Drugs that modulate the level of function of the channels may have little efficacy in patients with the SCA6 phenotype, since this disorder results from progressive cerebellar cell loss which is probably due to neurotoxicity of the polyglutamine peptide that is mutated in the disorder.
By a positional cloning approach, Fletcher et al. (1996) identified an alpha-1 voltage-sensitive Ca(2+) channel gene that is mutated in the 'tottering' mutations in tg and tg(la) mice. The tg mutation is a well-studied mutation that gives rise to behavioral arrest seizures, which may be compared to human absence (or petit mal) epilepsy (600131) and cerebellar ataxia. The tottering phenotype also includes motor seizures. Fletcher et al. (1996) noted that the tg leaner mice, tg(la), suffer from absence seizures but do not have motor seizures. These mice are severely ataxic. Fletcher et al. (1996) mapped the tg phenotype to mouse chromosome 8 in the vicinity of the Junb gene (165161). Fletcher et al. (1996) evaluated the Ca(2+) channel gene as a candidate for the tg locus using RT-PCR and sequencing. In the tg(la) mice they demonstrated a single G-to-A change in a splice donor site in the portion of the mouse gene encoding the putative regulatory C-terminal domain of the channel. This mutation resulted in several aberrant mRNA species, including insertion of 98 nucleotides at position 5901/2 and deletion of nucleotides 5763-5901, either of which altered the reading frame 3-prime to the mutations. The tg transcript contained a C-to-A transversion at position 1802 relative to the control sequence. Fletcher et al. (1996) reported that this alteration leads to a nonconservative proline-to-leucine amino acid substitution that may affect the pore function of the Ca(2+) channel. Fletcher et al. (1996) noted that this is the first gene identified as being involved in absence epilepsy.
The alpha-1 voltage-sensitive Ca(2+) channel sequence reported by Fletcher et al. (1996) is the mouse homolog of the human Ca(2+) channel alpha subunit, also designated CACNL1A4. It is noteworthy that the CACNL1A4 gene maps to chromosome 19p13 in a region that is homologous to the region of mouse chromosome 8 where tg maps.
In a provocatively entitled minireview, 'Migraines in Mice?,' Hess (1996) compared the tottering/leaner mouse mutations with the human mutations in CACNL1A4. She referred to inherited ion channel mutations as channelopathies.
Thibault and Landfield (1996) used partially dissociated hippocampal slice preparations to analyze single Ca(2+) channel activity in neurons of adult and aged rats. They reported that total L-type Ca(2+) channel activity increased primarily because of increased density of functional channels. They noted that learning in aged animals was inversely correlated with channel density. Thibault and Landfield (1996) postulated that the observed increase in functional Ca(2+) channels with aging could underlie the vulnerability of neurons to age-associated neurodegenerative conditions.
Van den Maagdenberg et al. (2004) generated a transgenic mouse model carrying the human CACNA1A mutation R192Q (601011.0001). Cultured cerebellar granule cells from R192Q mice showed increased Ca(v)2.1 channel current densities, which were activated at more negative voltages than wildtype channels. Neuromuscular synapses with the mutant CACNA1A channels had increased induced neurotransmission and increased spontaneous miniature endplate potential frequency at low Ca(2+) levels compared to controls, consistent with a gain of function. In addition, the intact transgenic animal showed increased susceptibility to cortical spreading depression, the likely mechanism for migraine aura. Van den Maagdenberg et al. (2004) concluded that the underlying mechanism in FHM is cortical hyperexcitability due to excessive release of excitatory amino acids in response to increased Ca(2+) influx through a defective Ca(v)2.1 channel.
Near postnatal day 10, mice lacking P/Q-type calcium channels have difficulty walking, have absence seizures, and are ataxic and dystonic. Neurologic symptoms in these mice become more acute with age, until they are unable to walk and die at about 3 weeks of age (Jun et al., 1999). Mutant animals also show increased density of T-type channels (CACNA1G; 604065) that support low-threshold action potentials in the absence of P/Q-type channels (Song et al., 2004). Llinas et al. (2007) found that in vitro patch recordings of thalamic neurons from mice lacking P/Q-type channels showed no gamma band subthreshold oscillation, and voltage-sensitive dye imaging demonstrated absence of cortical gamma band-dependent columnar activation involving cortical inhibitory interneuron activity. In vivo EEGs showed persistent absence status and dramatically reduced gamma band activity. Pharmacologic blockade of T-type channels left knockout mice in a coma-like state, indicating that increased T-type channel expression in thalamocortical neurons was causally related to generation of absence seizures. Llinas et al. (2007) concluded that P/Q-type calcium channels are essential for generation of gamma band activity and resultant cognitive function.
Watase et al. (2008) found that knockin mice expressing a hyperexpanded polyglutamine (84Q) Cacna1a repeat developed progressive motor impairment consistent with SCA6. Knockin mice with normal 14 CAG or expanded 30 CAG repeats did not show such defects. Electrophysiologic analysis of cerebellar Purkinje cells revealed similar calcium channel current density among the 3 mouse models, although all were decreased compared to wildtype due to decreased channel abundance. Neither voltage sensitivity of activation nor inactivation was altered in the Sca6(84Q) neurons, suggesting that the expanded CAG repeat does not per se affect the intrinsic electrophysiologic properties of the channels. Mice with the hyperexpanded polyglutamine repeat showed cytoplasmic neuronal inclusions, consistent with aggregation of mutant calcium channels. Watase et al. (2008) concluded that the pathogenesis of SCA6 is related to an age-dependent process accompanied by accumulation of mutant CACNA1A channels resulting in a toxic gain-of-function effect.
Van Oosterhout et al. (2008) found that R192Q-mutant mice showed atypical phase resetting of their circadian rhythms when subjected to 6-hour advance shifts of the light/dark cycle. Compared to controls, mutant mice showed a more than 2-fold enhanced adjustment of behavioral wheel-running activity and EEG patterns, as well as enhanced shifts of electrical activity of suprachiasmatic neurons (SCN) in vivo. No differences were observed for a 6-hour delay. The physiologic inhibitory process appeared to be mediated by CACNA1A channel-dependent afferent signaling from extra-SCN brain areas to the SCN. Van Oosterhout et al. (2008) interpreted the findings as suggesting that abrupt circadian rhythm changes may trigger migraine attacks, possibly because patients have an inadequate adaptation mechanism.
Eikermann-Haerter et al. (2009) found that transgenic mice expressing the R192Q or S218L (601011.0017) CACNA1A mutations had increased frequency and speed of spreading depression and enhanced corticostriatal propagation compared to wildtype mice after induction. Mutant mice also developed severe and prolonged neurologic deficits. The susceptibility to spreading depression and neurologic deficits was affected by allele dosage and was higher in S218L than R192Q mutants, similar to observations in humans. Female mutant mice were more susceptible to spreading depression and neurologic deficits than males, and this sex difference was abrogated by ovariectomy or senescence and partially restored by estrogen replacement. The findings implicating ovarian hormones in the observed sex differences in humans with FHM1. In a follow-up study, Eikermann-Haerter et al. (2009) demonstrated that orchidectomy in R192Q-mutant male mice increased susceptibility to cortical spreading depression, and that chronic testosterone replacement restored the lower susceptibility in mutant males. These findings implicated androgens as a modulating factor in genetically-enhanced susceptibility to cortical spreading depression.
Van den Maagdenberg et al. (2010) found that transgenic S218L homozygous mice had mild cerebellar ataxia and reduced arborization of proximal primary dendrites of cerebellar Purkinje neurons. They exhibited 2 types of spontaneous attacks: those consistent with hemiparesis observed in patients with FHM1 and attacks of generalized seizures that were fatal in some cases. In addition, homozygous mutant mice developed significant brain edema 24 hours after mild head impact, indicating that these mice mimicked the broad complex neurologic spectrum of spontaneous episodic, mild impact-triggered, and permanent clinical features seen in human patients heterozygous for the S218L mutation. In vitro studies on mouse cerebellar granule neurons showed that the S218L mutation increased whole-cell calcium current density at negative voltages, resulted in a leftward shift in voltage-dependent activation, and increased spontaneous neurotransmitter release, consistent with a gain of function. The calcium current in homozygous mutant cells was 6.6 times greater than that in wildtype neurons. Further studies showed that mutant mice had an increased susceptibility to successive cortical spreading depression events compared to wildtype and mutant R192Q mice. In general, all of the changes associated with the S218L mutation were quantitatively more pronounced than those observed with the R192Q mutation.
Du et al. (2013) found that expression of alpha-1act partially improved the phenotype of Cacna1a-null mice and provided a modest improvement in survival. Expression of alpha-1act also partially improved synaptic activity and connections in Cacna1a-null cerebellar slice preparation. Alpha-1act with a pathologic polyQ expansion reduced viability of PC12 cells in culture and mediated ataxia and cerebellar cortical atrophy in transgenic mice.
By characterizing a dose-dependent Cacna1a gene deficiency mouse model, Du et al. (2019) found that alpha-1Act drove dynamic gene regulation networks within cerebellar Purkinje cells and was indispensable for neonatal survival. Perinatal loss of alpha-1Act disrupted neurogenesis and synaptic regulatory networks, leading to motor dysfunction. In contrast, elimination of alpha-1Act in adulthood had minimal effects on cerebellum. The authors demonstrated a similar age-dependent pattern of alpha-1ACT gene regulation in human cerebellum, validating their observations in mouse cerebellum.
In 5 unrelated families with familial hemiplegic migraine (FHM1; 141500), Ophoff et al. (1996) identified 4 different missense mutations in the CACNL1A4 gene. One of these mutations was a G-to-A transition at nucleotide 850 in exon 4 resulting in an arg192-to-gln (R192Q) amino acid substitution.
In families with hemiplegic migraine (FHM1; 141500), Ophoff et al. (1996) discovered a C-to-T transition in nucleotide 2272 of CACNL1A4, resulting in a thr666-to-met (T666M) amino acid substitution.
Friend et al. (1999) found this recurrent mutation in exon 16 in an Australian patient with familial hemiplegic migraine.
Ducros et al. (1999) screened 16 families and 3 nonfamilial cases with hemiplegic migraine associated with progressive cerebellar ataxia (see 141500). They found the T666M mutation in 9 families and 1 nonfamilial case. The T666M mutation was absent in 12 probands belonging to pure HPM families whose disease appeared to be linked to CACNA1A.
Terwindt et al. (2002) studied 27 patients with sporadic hemiplegic migraine and found the T666M mutation in a 78-year-old woman who had characteristic attacks starting at age 14 as well as interictal nystagmus, dysarthria, limb and gait ataxia, and cerebellar atrophy.
Kors et al. (2003) reported the clinical symptoms of 5 families with hemiplegic migraine and the T666M mutation. Three of the families displayed cerebellar ataxia, 3 had loss of consciousness or coma associated with episodes, 1 had attacks with confusion but without hemiparesis, and 1 had progressive cognitive dysfunction. The authors emphasized the inter- and intrafamilial clinical heterogeneity.
Barrett et al. (2005) found that CACNA1A channels with the T666M mutation were expressed and trafficked normally to the cell surface in transfected HEK293 cells. However, T666M mutant channels exhibited defective voltage-dependent gating to support calcium influx.
In families with hemiplegic migraine (FHM1; 141500), Ophoff et al. (1996) identified a T-to-C transition in nucleotide 2416 of the CACNL1A4 gene, resulting in a val714-to-ala (V714A) amino acid substitution.
In 2 unrelated families, Ophoff et al. (1996) found that members with hemiplegic migraine (FHM1; 141500) had an A-to-C transversion at nucleotide 5706 of the CACNL1A4 gene, resulting in an ile1811-to-leu (I1811L) amino acid substitution in the gene product. The mutation occurred on different 19p13 haplotypes in the 2 families, indicating that this was a recurrent mutation rather than a founder effect. Cerebellar atrophy is said to occur in approximately 40% of chromosome 19-linked HPM families but not in unlinked HPM families (Terwindt et al., 1996). Of the 2 families with the I1811L mutation, Ophoff et al. (1996) noted that only 1 displayed cerebellar atrophy and in that family only some members were affected. Apparently other factors in this amino acid substitution further contribute to the phenotypic variability. These factors may include genetic polymorphisms elsewhere in the gene or at other channel-related loci and the net effect of other ion channels on the polarity of the cell membrane.
In 2 unrelated patients with episodic ataxia type 2 (EA2; 108500), Ophoff et al. (1996) identified mutations resulting in a disrupted reading frame. The first of these was deletion of a single C, nucleotide 4073 in codon 1266, leading to a frameshift in the putative translation product with a stop codon in the next exon (codon 1294). See also 601011.0006.
In a patient with episodic ataxia type 2 (EA2; 108500), Ophoff et al. (1996) identified a G-to-A transition in the first nucleotide of intron 24, changing the highly conserved GT dinucleotide of the intronic 5-prime splice junction. The mutation resulted in the loss of a BsaAI restriction site. The brain-specific expression of CACNL1A4 precluded testing the hypothesis that this mutation produced aberrantly spliced RNAs by retaining the intron or utilizing other cryptic 5-prime splice sites. Such was, however, presumably the case.
Zhuchenko et al. (1997) identified expansion of a CAG repeat predicted to encode for polyglutamine in exon 47 of the coding region of the CACNL1A4 gene in families with slowly progressive spinocerebellar ataxia designated SCA6 (183086).
Matsuyama et al. (1997) analyzed 60 SCA6 individuals from 39 independent Japanese SCA6 families and found that the CAG repeat length in the CACNL1A4 gene was inversely correlated with age of onset. SCA6 chromosomes contained 21 to 30 repeat units, whereas normal chromosomes displayed 6 to 17 repeats. There was no overlap between the normal and affected CAG repeat number. Anticipation was observed clinically in all 8 parent-child pairs examined; the mean age of onset was significantly lower (P = 0.0042) in children than in parents. However, a parent-child analysis showed an increase in the expansion of CAG repeats only in 1 pair and no diminution in any affected cases. The results suggested that factors other than CAG repeats may produce the clinical anticipation. A homozygotic case could not demonstrate unequivocal gene dosage effect on the age of onset. See also Ishikawa et al. (1997).
Riess et al. (1997) found that the SCA6 mutation accounts for approximately 10% of autosomal dominant SCA in Germany. They observed the trinucleotide expansion in 4 ataxia patients without obvious family history of the disease, indicating the necessity to search for the SCA6 (CAG)n expansion even in sporadic patients. In their series of 32 patients, onset was usually late and the (CAG)n stretch varied between 22 and 28 trinucleotide units, the shortest trinucleotide repeat expansion causing spinocerebellar ataxia. Analyzing 248 apparently healthy octogenarians, Riess et al. (1997) found 1 allele of 18 repeats, the longest normal CAG repeat in the CACNL1A4 gene reported to that time. They could demonstrate no repeat instability of the expanded allele on transmission and no repeat instability was found for the normal allele in 431 meioses in the CEPH families.
Sasaki et al. (1998) described neuropathologic and molecular findings in a Japanese woman who died of lymphoma at the age of 61 years after a 7-year history of progressive pure cerebellar ataxia. Neuropathologic examination showed neuronal degeneration confined to the cerebellar Purkinje cells and, to a lesser degree, the granular cells, without involvement of other CNS structures. The pathologic selectivity correlated with the localized expression of the CACNA1A gene and coincided with the neurologic manifestations. The father and a sister were also affected. Each of the affected sisters was heterozygous for an expanded allele with a repeat size that fell into the range of the SCA6 mutation.
Using a whole-cell voltage clamp technique, Toru et al. (2000) demonstrated functional alterations of human alpha-1A channels carrying various polyglutamine lengths in a model of SCA6. Alpha-1A channels lacking an asparagine-proline (NP) stretch in domain IV corresponded to P-type channels expressed in Purkinje cells, the main cell that is degenerated in SCA6. Polyglutamine elongation caused a proportional negative shift of voltage-dependent inactivation, and the authors hypothesized that the resulting reduction of calcium influx may contribute to Purkinje cell death.
Kordasiewicz et al. (2006) found that the 75-kD C-terminal fragment of CACNA1A, which is the location of the polyglutamine tract expanded in SCA6, was translocated to the nucleus, where it was toxic to cells when in the expanded state. The polyglutamine-mediated cell toxicity was dependent on nuclear localization, suggesting that specific processing and localization of the mutant protein are involved in the pathogenesis of SCA6.
Li et al. (2009) found that HEK293 cells expressing an expanded (24 CAG repeats) C-terminal CACNA1A fragment showed decreased viability when exposed to toxic cadmium compared to cells with nonexpanded (13 CAG) repeats. However, there were no differences in viability under normal culture conditions. Cadmium treatment also disrupted PMLNBs and enhanced aggregation of C-terminal CACNA1A fragments, particularly in CAG-expanded cells. Immunocytochemical studies showed that cadmium-induced death was caspase-3 (CASP3; 600636)-dependent, indicating apoptosis. Gene expression studies showed downregulation of the HSF1 (140580)-HSPA1A (140550) axis as an event in 24-CAG repeat cells that appeared to be critical for cellular toxicity. The findings were consistent with SCA6 pathogenesis being related to polyglutamine diseases.
Du et al. (2013) found that expression of alpha-1ACT containing a pathologic polyQ expansion did not induce neurite outgrowth in PC12 cells and was unable to induce expression of genes targeted by wildtype alpha-1ACT.
Craig et al. (2008) identified a common core haplotype carrying the CACNA1A CAG repeat in 45 SCA6 families from different geographic regions, including Europe, Brazil, and Japan. The haplotype was also present in the unaffected father of a proven de novo Japanese patient, suggesting that the shared chromosome predisposes to the CAG repeat expansion at the SCA6 locus. The SCA6 expansion lies immediately downstream of a CpG island, which could act as a cis-acting element predisposing to repeat expansion, as observed for other CAG/CTG repeat diseases.
In a family with a clinical diagnosis of episodic ataxia-2 (EA2; 108500), Jodice et al. (1997) found a (CAG)23 repeat allele segregating in patients showing different interictal symptoms, ranging from nystagmus only to severe progressive cerebellar ataxia. No additional mutations in coding and intron-exon junction sequences in disequilibrium with the CAG expansion were found. In a second family, initially classified as autosomal dominant cerebellar ataxia of unknown type, an intergenerational allele size change showed that a (CAG)20 allele was associated with an EA2 phenotype and a (CAG)25 allele with progressive cerebellar ataxia. These results suggested that EA2 and SCA6 (183086) are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggested that the small expansions may not be as stable as previously reported. See also 601011.0007.
Yue et al. (1997) studied a family in which multiple members had severe progressive cerebellar ataxia involving the trunk, extremities, and speech (SCA6; 183086). The proband started at age 15 years with gradual onset of imbalance and incoordination. Slurred speech was first noted in her twenties. She became confined to a wheelchair at the age of 44 years. By that time prominent atrophy of the cerebellum was demonstrated by magnetic resonance imaging. Two sons had episodes of vertigo and ataxia that were not responsive to acetazolamide, consistent with episodic ataxia type 2 (EA2; 108500). Quantitative eye movement testing showed a consistent pattern of abnormalities localized to the cerebellum. Genotyping suggested linkage to 19p, and SSCP showed an aberrant migrating fragment in exon 6 of the CACNA1A gene which cosegregated with the disease. Sequencing of exon 6 identified a G-to-A transition in 1 allele, at nucleotide 1152, resulting in a predicted gly293-to-arg amino acid substitution. The CAG-repeat expansion associated with SCA6 (601011.0007) was not present in any family member. Yue et al. (1997) indicated that replacement of a neutral amino acid (glycine) with a positively charged amino acid (arginine) near the center of the pore in domain I would likely lead to a distortion of the pore region. Two patients in the family had prominent ataxic episodes, whereas the other 2 patients had no episodes, suggesting that other factors such as modifying genes or metabolic factors such as hormone levels may be important in determining susceptibility to episodic dysfunction. On the other hand, all 4 patients exhibited gradually progressive ataxia, indicating that this pore mutation resulted in chronic increased intracellular calcium, ultimately leading to neuronal death.
Wan et al. (2005) performed functional expression studies of the G293R mutation in the family reported by Yue et al. (1997) and the adjacent C287Y mutation (601011.0025).
In affected members of a family (F10) with hemiplegic migraine associated with progressive cerebellar ataxia (see 145000), Ducros et al. (1999) identified C-to-G transversion in the CACNA1A gene, resulting in an asp715-to-glu (D715E) mutation.
Friend et al. (1999) found a 5260G-A transition in exon 32 of the CACNA1A gene, resulting in an arg1666-to-his amino acid substitution, in a patient with episodic ataxia (EA2; 108500). The amino acid substitution occurred in a highly conserved position within the gene. This represented the first point mutation that did not result in a proposed truncated protein. One member of the family, who had inherited both the mutation and the affected haplotype, had no clinical evidence of cerebellar dysfunction. On examination, he had no signs of nystagmus on lateral gaze, and his balance and cerebellar examination were within normal limits. He did, however, experience migraines.
Guida et al. (2001) reported the first functional analysis of a novel missense mutation associated with an EA2 phenotype: a T-to-C transition at nucleotide 4747 in exon 28 of the CACNA1A gene, predicted to change a highly conserved phenylalanine residue to a serine at codon 1491, located in the putative transmembrane segment S6 of domain III. Patch-clamp recording in HEK 293 cells, coexpressing the mutagenized human alpha-1A subunit, together with the human beta and alpha-delta subunits, showed that channel activity was completely abolished, although the mutated protein was expressed in the cell. These results indicated that a complete loss of P/Q channel function is the mechanism underlying EA2, whether due to truncating or to missense mutations.
In a patient with hemiplegic migraine associated with coma, hyperthermia, meningeal signs, and partial seizures, Vahedi et al. (2000) identified a de novo A-to-G transition (TAC to TGC) at codon 1385 of the CACNA1A gene, resulting in a tyrosine-to-cysteine amino acid substitution in the alpha-1A subunit of the P/Q-type calcium channel. The mutation was not detected in 200 control chromosomes or in either of the healthy parents, suggesting that the mutation is not a polymorphism. The mutation is in the highly conserved segment 5 of the third domain of the calcium channel, an area previously shown to be important in familial hemiplegic migraine (Ophoff et al., 1996; Ducros et al., 1999).
In 4 members of a family with onset of episodic ataxia type 2 (EA2; 108500) after age 30, Denier et al. (2001) identified a G-to-A change in exon 35 of the CACNA1A gene, resulting in a glu1757-to-lys substitution. The authors did not detect the mutation in 200 control chromosomes. The mutation affects a highly conserved amino acid located in the pore loop, which plays a major role in the function of the channel.
Scoggan et al. (2001) identified a 1-bp insertion at nucleotide 3091 of the CACNA1A gene (3091insG) in an individual with episodic ataxia type 2 (EA2; 108500). Scoggan et al. (2001) believed this to be the first mutation identified to occur in an intracellular loop of the CACNA1A protein.
Scoggan et al. (2001) identified a 1-bp deletion at nucleotide 5123 of the CACNA1A gene (5123delG) in an individual with episodic ataxia type 2 (EA2; 108500). Scoggan et al. (2001) believed this to be the most 3-prime CACNA1A mutation reported to that time.
Noting that familial hemiplegic migraine (FHM1; 141500) can be triggered by minor head trauma, Kors et al. (2001) investigated a role for CACNA1A in 'delayed cerebral edema,' a severe, sometimes even fatal, cerebral edema and coma occurring after a lucid interval as a result of trivial head trauma. In 2 patients with the phenomenon from a family with extreme familial hemiplegic migraine and in 1 patient whose parent had familial hemiplegic migraine and whose family suffered from various neurologic abnormalities, Kors et al. (2001) identified heterozygosity for a mutation in the CACNA1A gene, resulting in the replacement of a hydrophilic serine for a hydrophobic leucine at residue 218 (S218L) in the highly conserved intracellular loop of the alpha-1A subunit. The authors suggested a pathogenic mechanism involving ionic perturbation resulting from inappropriately depolarized ion channels.
Chan et al. (2008) reported 3 Malaysian sibs with FHM1 due to heterozygosity for a 935C-T transition in exon 5 of the CACNA1A gene, resulting in the S218L mutation. The phenotype of the hemiplegic migraine episodes was severe in the older brother and sister, each of whom became comatose on at least 1 occasion. A history of generalized seizures was associated with mild head trauma in the older boy and with febrile illness in the younger boy. The older brother and sister also had cerebellar atrophy on brain MRI. EEG studies of them during hemiplegic attacks showed evidence of depressed cortical activity contralateral to the hemiparesis, perhaps representing cortical spreading depression due to a defect in calcium channel activity.
Developmental and Epileptic Encephalopathy 42
In a girl (patient T21924) with developmental and epileptic encephalopathy-42 (DEE42; 617106), the Epi4K Consortium (2016) identified a heterozygous c.653C-T transition (c.653C-T, NM_023035.2) in the CACNA1A gene, resulting in a ser218-to-leu (S218L) substitution. Functional studies of the variant and studies of patient cells were not performed. The mutation was not found in the unaffected mother; DNA from the unaffected father was not available. The authors considered this change to be a variant of unknown significance, noting that it had previously been found in a patient with familial hemiplegic migraine with progressive cerebellar ataxia.
In 2 Italian sisters with familial hemiplegic migraine (FHM1; 141500) and late-onset cerebellar ataxia and cerebellar atrophy, Battistini et al. (1999) identified an arg583-to-gln (R583Q) mutation in a putative voltage sensor domain of the CACNA1A gene. The frequency and severity of the attacks increased near the sixth decade for both patients, when the cerebellar signs developed. Acetazolamide was effective prophylactic therapy.
Terwindt et al. (2002) studied 27 patients with sporadic hemiplegic migraine and found the R583Q mutation in a 16-year-old boy with no cerebellar signs.
In a large Portuguese family in which 17 patients over 4 generations were affected with hemiplegic migraine and/or progressive cerebellar ataxia-6 (SCA6; 183086), Alonso et al. (2003) found that all patients shared a common haplotype and carried the R583Q mutation. Mean age at onset for hemiplegic migraine symptoms was in the second decade and onset of cerebellar signs was approximately 20 years later. Four patients, all under the age of 18 years, had only hemiplegic migraine, 8 patients had isolated progressive cerebellar ataxia, and 5 patients had both hemiplegic migraine and cerebellar ataxia. Several patients reported symptoms triggered by minor head trauma. Alonso et al. (2003) postulated that the mutation, which occurs in a transmembrane segment of the voltage sensor of the channel, may cause a shift in the voltage dependence of the channel, leading to an increase in intracellular calcium. They suggested that episodic ataxia-2 (EA2; 108500), SCA6, and familial hemiplegic migraine are not only allelic disorders, but may be the same disorder with great phenotypic variability.
De Vries et al. (2007) identified a 2021G-A transition in the CACNA1A gene, resulting in an R583Q substitution, in a patient who developed FHM at age 13 years. The mutation was also identified in his mother, who had migraine with aura. The findings suggested either reduced penetrance or a common pathogenetic mechanism for both hemiplegic and nonhemiplegic migraine.
In a 5-generation Caucasian family originating from northeastern Italy, in which the average age of onset of familial hemiplegic migraine (FHM1; 141500) was 33.8 years, Carrera et al. (1999) found a G-to-T transversion at nucleotide position 4644 in exon 27 of the CACNA1A gene, which resulted in a val1457-to-leu (V1457L) amino acid substitution. All patients had clinical symptoms preceded by aura, followed by hemiparesis and various degrees of aphasia congruent with the hemispheric dominance of each individual. Patients did not report cerebellar ataxia or coma. Carrera et al. (1999) noted that the location of the mutation, in the putative pore-forming (P) region between the S5-S6 transmembrane domains in motif III of CACNA1A, suggests a potential for interference in transmembrane conductance.
Yue et al. (1998) reported a patient with episodic ataxia type 2 (EA2; 108500) who carried a 4410C-T substitution in exon 23 of the CACNA1A gene, resulting in an arg1281-to-ter (R1281X) mutation that predicts a truncated product containing only the first 2 domains of the protein. The patient experienced attacks of vertigo, truncal and limb ataxia, nystagmus, and diffuse weakness during ataxic spells.
By use of whole-cell patch-clamp recordings, Jen et al. (2001) demonstrated that the R1281X, R1549X (601011.0021), and F1406C (601011.0022) mutations, when expressed in COS-7 cells, resulted in markedly diminished barium current density and amplitude compared with the wildtype gene. They used single-fiber EMG (SFEMG) recordings to examine synaptic transmission at the neuromuscular junction in the 3 patients who carried these mutations, all of whom complained of episodic weakness. The SFEMG demonstrated abnormal neuromuscular transmission in vivo, suggesting that these mutations contributed to the symptoms of weakness described by the patients.
Jen et al. (1999) reported affected members of a family with episodic ataxia type 2 (EA2; 108500) who carried a 4914C-T substitution in exon 29 of the CACNA1A gene. The substitution resulted in an arg1549-to-ter (R1549X) mutation (reported in the article as ARG1547TER) that predicts a truncated product containing the first 3 domains of the protein. The patients experienced attacks of vertigo, truncal and limb ataxia, nystagmus, and diffuse weakness during ataxic spells. See also 601011.0020.
Jen et al. (2001) reported a patient with episodic ataxia type 2 (EA2; 108500) who also developed progressive episodic weakness beginning in his teens. Mutation analysis revealed a 4486T-G change in exon 26 of the CACNA1A gene, resulting in a phe1406-to-cys (F1406) change in the putative P loop of the protein between domains 3 and 4, which may disrupt pore formation. See also 601011.0020.
In an isolated case of a boy with seizures, episodic ataxia type 2 (EA2; 108500), and interictal progressive cerebellar signs, Jouvenceau et al. (2001) identified a heterozygous 5733C-T transition in the CACNA1A gene, resulting in a premature stop codon (arg1820 to ter; R1820X) between the last transmembrane segment (IVS6) and the intracellular C terminus of the mature protein. Functional expression studies indicated a dominant-negative effect on channel conductance. Jouvenceau et al. (2001) noted that mouse models of absence epilepsy and cerebellar degeneration harbor mutations in the CACNA1A gene.
Holtmann et al. (2002) reported a family in which a father and daughter had idiopathic focal epilepsy, episodic ataxia type 2, and migraine. Four other family members had migraine, and 2 had reported seizures. Holtmann et al. (2002) suggested that the cooccurrence of periodic neurologic disorders in their family was similar to that in the case presented by Jouvenceau et al. (2001).
In a mother and her 2 adult children who had familial hemiplegic migraine (FHM1; 141500) and childhood-onset of cerebellar ataxia (SCA6; 183086), Kors et al. (2004) identified a heterozygous 5405T-C transition in exon 33 of the CACNA1A gene, resulting in an ile1710-to-thr (I1710T) substitution within transmembrane segment 5 of the fourth domain of the protein. Kors et al. (2004) stated that the affected residue is strongly conserved. In addition to FHM1 and SCA6, both children had complex partial and generalized tonic-clonic seizures that occurred independently of the FHM attacks and were restricted to childhood.
In affected members of a family with episodic ataxia type 2 (EA2; 108500) and mild baseline ataxia, Wan et al. (2005) identified a 1096G-A transition in exon 6 of the CACNA1A gene, resulting in a cys287-to-tyr (C287Y) substitution in the putative P loop between transmembrane segments S5 and S6 within domain I of the protein. The mutation is adjacent to another mutation, G293R (601011.0009), in the same region of the protein. Functional expression studies of both mutations indicated that the mutant channels exhibited decreased current densities (31 to 35% of wildtype), which were partially restored by cooling. Immunofluorescence studies showed that the mutant proteins accumulated in the endoplasmic reticulum. The findings suggested that the mutations caused misfolding and altered trafficking of the protein, resulting in a defect in plasma membrane targeting. Once expressed at the cell surface, the mutant channels were able to conduct current but with altered biophysical properties. Wan et al. (2005) hypothesized that the episodic features of EA2 result from altered channel function, while the interictal features result from protein mishandling, eventually leading to cerebellar neuronal death.
In 3 affected members of a family with episodic ataxia type 2 (EA2; 108500), Riant et al. (2008) identified a heterozygous 39.5-kb deletion in the CACNA1A gene, resulting in the removal of the last 16 coding exons of the gene. Sequence analysis of the deletion boundaries suggested that the deletion arose through homologous recombination of Alu sequences.
In affected members of 4 unrelated families with familial hemiplegic migraine-1 (FHM1; 141500), Stam et al. (2008) identified a heterozygous 4040G-A transition in exon 25 of the CACNA1A gene, resulting in an arg1347-to-gln (R1347Q) substitution in the S4 segment of protein domain III. Haplotype analysis excluded a founder effect. In 3 of the 4 families, age at onset was before age 3 years. Two patients in 1 family also had focal seizures. Stam et al. (2008) stated that the R1347Q mutation was the third most common CACNA1A mutation associated with FHM1, after T666M (601011.0002) and R583Q (601011.0018).
In 2 affected members of a family with episodic ataxia type 2 (EA2; 108500), Labrum et al. (2009) identified a heterozygous 146.1-kb deletion in the CACNA1A gene, resulting in deletion of exon 4 Exon 4 encodes the S4 voltage sensor segment of domain I and the removal of this exon is likely to have deleterious effects on kinetic parameters, such as the voltage dependence of activation. The deletion was not detected in a panel of 180 normal control chromosomes.
In 8 affected members of a 4-generation family with episodic ataxia type 2 (EA2; 108500), Labrum et al. (2009) identified a heterozygous 35.7-kb deletion in the CACNA1A gene, resulting in deletion of exon 6. The deletion was not identified in an unaffected member of this family or in a panel of 180 normal control chromosomes.
In an index patient with isolated episodic diplopia without ataxia, Labrum et al. (2009) identified a heterozygous 35.7-kb duplication in the CACNA1A gene, resulting in duplication of exon 6. The patient's father reportedly had typical episodic ataxia type 2 (EA2; 108500). The duplication was not detected in a panel of 180 normal control chromosomes.
In a proband with episodic ataxia type 2 (EA2; 108500), Labrum et al. (2009) identified a heterozygous 7.4-kb deletion in the CACNA1A gene, resulting in deletion of exon 27. The deletion was not detected in a panel of 180 normal control chromosomes.
In a proband with episodic ataxia type 2 (EA2; 108500), Labrum et al. (2009) identified a heterozygous 86.1-kb deletion in the CACNA1A gene, resulting in deletion of exons 20 to 38. The deletion was not detected in a panel of 180 normal control chromosomes.
In 2 unrelated patients with episodic ataxia type 2 (EA2; 108500), Labrum et al. (2009) identified a heterozygous 18.2-kb deletion in the CACNA1A gene, resulting in deletion of exons 39 to 47. The deletion was not detected in a panel of 180 normal control chromosomes.
In a patient with sporadic hemiplegic migraine (FHM1; 141500), Labrum et al. (2009) identified a heterozygous 18.2-kb deletion in the CACNA1A gene, resulting in deletion of exons 39 to 47. The deletion was not detected in a panel of 180 normal control chromosomes.
In a 4-year-old boy (patient EG1371) with developmental and epileptic encephalopathy-42 (DEE42; 617106), the Epi4K Consortium (2016) identified a de novo heterozygous c.301G-C transversion (c.301G-C, NM_023035.2) in the CACNA1A gene, resulting in a glu101-to-gln (E101Q) substitution. Functional studies of the variant and studies of patient cells were not performed. He had onset of tonic seizures at 4 weeks of age. EEG showed epilepsy of infancy with migrating focal seizures (EIMFS).
In 2 unrelated patients (patients T23039 and T24139) with developmental and epileptic encephalopathy-42 (DEE42; 617106), the Epi4K Consortium (2016) identified a heterozygous c.2137G-A transition (c.2137G-A, NM_023035.2) in the CACNA1A gene, resulting in an ala713-to-thr (A713T) substitution. The mutation in 1 patient occurred de novo, where the mutation in the other patient and his similarly affected sib (patient T24629) was inherited from the unaffected mother who was somatic mosaic for the mutation (6.3% mutational load in the mother's lymphocytes). The same mutation had also been identified in a patient with DEE42 by the EPI4K Consortium and Epilepsy Phenome/Genome Project (2013). Functional studies of the variant and studies of patient cells were not performed. The patients had onset of seizures in the neonatal period.
In a girl (patient EG1519) with developmental and epileptic encephalopathy-42 (DEE42; 617106), the Epi4K Consortium (2016) identified a de novo heterozygous c.4531G-T transversion (c.4531G-T, NM_023035.2) in the SLC1A2 gene, resulting in an ala1511-to-ser (A1511S) substitution. The mutation was not found in the Exome Sequencing Project, 1000 Genomes Project, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed. The patient had onset of status epilepticus on the first day of life.
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