Disease relevance of CACNA1A

• Familial hemiplegic migraine type 1 (FHM-1) is a Mendelian subtype of migraine with aura that is caused by missense mutations in the CACNA1A gene that encodes the alpha(1) subunit of neuronal Ca(v)2.1 Ca(2+) channels [1].
• Familial hemiplegic migraine, a rare Mendelian form of MA, can be caused by mutations in the calcium channel gene, CACNA1A or in the ATP1A2 gene, a Na+/K+ pump [2].
• Novel CACNA1A mutation causes febrile episodic ataxia with interictal cerebellar deficits [3].
• These findings suggest that early cerebellar dysfunction in EA2 results from the intrinsically abnormal properties of the CACNA1A channel rather than a degenerative process [3].
• Episodic ataxia type 2 (EA2) is a dominantly inherited disorder, characterized by spells of ataxia, dysarthria, vertigo, and migraines, associated with mutations in the neuronal calcium-channel gene CACNA1A [3].

Psychiatry related information on CACNA1A

• Migraine is an episodic pain disorder whose pathophysiology is related to deficiency of serotonin signaling and abnormal function of the P/Q-type calcium channel, CACNA1A [4].
• Criterion validity was assessed against an independent structured mental health professional (MHP) interview in a sample of 580 patients [5].
• Patients with a MHP involved in their care were much more likely to present with psychosis and suicidal ideation in the absence of deliberate self-harm [6].
• 34 patients, suffered from a severe brain injury (BI) 4 to 8 years ago, were reexamined by a psychological test battery and by evaluating of QOL (using self developed items for private and social activity) [7].

High impact information on CACNA1A

• Additionally, pure cerebellar ataxias, which represent up to 20% of all ataxias, remain poorly studied with only two causative dominant genes being described: CACNA1A (ref. 9) and SPTBN2 (ref. 10) [8].
• We studied the various clinical manifestations associated with mutations in CACNA1A in families with hemiplegic migraine with and without cerebellar signs [9].
• Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel [10].
• We conclude that a small polyglutamine expansion in the human alpha 1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6 [10].
• Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4 [11].

Chemical compound and disease context of CACNA1A

• In all three subjects with delayed severe edema, we found a C-to-T substitution resulting in the substitution of serine for lysine at codon 218 (S218L) in the CACNA1A gene [12].
• A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia [13].
• No association between the main risk factors for BI such as hypertension, cholesterol, diabetes and MPO polymorphisms was found [14].
• The present study was designed to estimate the prognosis for patients admitted with threatened abortion on the basis of assays of serum estradiol (E2) and progesterone (P) and the demonstration of fetal heart movements (FHM) by ultrasound scanning [15].
• The effect of taurine on gastric hemorrhage and mucosal erosion in the brain ischemia (BI) is unknown [16].

Biological context of CACNA1A

• Up to 75% of FHM families have a mutation in the P/Q-type calcium channel Ca(v)2.1 subunit CACNA1A gene on chromosome 19p13 [17].
• INTERVENTIONS: All known exons and flanking introns of CACNA1A and ATP1A2 were subjected to denaturing high-performance liquid chromatography analysis of polymerase chain reaction-amplified genomic DNA [18].
• BACKGROUND: Mutations in CACNA1A, encoding a neuronal calcium channel subunit, and ATP1A2, encoding a catalytic subunit of a sodium-potassium-ATPase, have been found in some families with dominantly inherited hemiplegic migraine [18].
• Studies on the genetics of familial hemiplegic migraine revealed, in addition to the previously identified familial hemiplegic migraine type 1 gene CACNA1A on chromosome 19, the familial hemiplegic migraine type 2 gene ATP1A2, encoding the alpha2-subunit of sodium/potassium pumps [19].
• A possible role for CACNA1A in producing the phenotype in this family was excluded by linkage studies to the FHM1 locus [20].

Anatomical context of CACNA1A

• The pore-forming, voltage-sensing transmembrane alpha-1 subunit of the P/Q voltage-gated calcium channel (or Ca(v)2.1) encoded by the CACNA1A gene is another major component of the process of action potential-evoked exocytosis at the adult mammalian neuromuscular junction [21].
• In SCA-3, abnormal ataxin-3 is aggregated in neuronal nuclei, and in SCA-6, a mutated alpha1A-calcium channel protein is the likely cause of abnormal calcium channel function in Purkinje cells and in the death of these neurons [22].
• In cultured cells, formation of perinuclear aggregates of the channel protein and apoptotic cell death were seen when transfected with full-length CACNA1A coding an expanded polyglutamine tract [23].
• Otolith function in cerebellar ataxia due to mutations in the calcium channel gene CACNA1A [24].
• The lack of pathological changes in the corticospinal tract of patients with SCA6 indicates that this abnormality may be caused by crossed cerebellar diaschisis, or a functional disorder in the brain resulting from CACNA1A mutations [25].

Associations of CACNA1A with chemical compounds

• FHM mutations so far identified include those in CACNA1A (P/Q voltage-gated Ca(2+) channel), ATP1A2 (N(+)-K(+)-ATPase) and SCN1A (Na(+) channel) genes [26].
• Mutant gene products of both CACNA1A and ATP1A2 may affect neurotransmission of glutamate, the most abundant excitatory amino acid neurotransmitter [27].
• Together with our previous finding that the polyglutamine expansion in SCA6 interferes with the Ca2+ channel to reduce Ca2+ influx, these results indicate that impaired function of the mutant Ca2+ channels rendered them unable to prevent cell death [28].
• The thyrotropin-releasing hormone, D-cycloserine, and acetazolamide for SCA6 may have some efficacy [29].
• This patient carried a de novo Tyr 1385 Cys mutation in the CACNA1A gene and illustrates a novel phenotype associated with CACNA1A mutations [30].

Other interactions of CACNA1A

• Episodic ataxia type 1 (EA-1) is caused by missense mutations in the potassium channel gene KCNA1, whereas episodic ataxia type 2 (EA-2) is caused by missense and nonsense mutations in the calcium channel gene CACNA1A [31].
• Genetic studies on migraine suggested a role of CACNA1A and DRD2 genes as susceptibility genes in this disorder [32].
• Furthermore, we sequenced all exons and promoter regions of the CACNA1A and ATP1A2 genes and screened for the Q1489K mutation in the SCN1A gene [33].
• Association between the alpha(1a) calcium channel gene CACNA1A and idiopathic generalized epilepsy [34].
• Two novel CACNA1A gene mutations associated with episodic ataxia type 2 and interictal dystonia [35].

Analytical, diagnostic and therapeutic context of CACNA1A

• The CACNA1A gene was screened by heteroduplex analysis and sequencing for mutations [35].
• To determine whether the CACNA1A gene was implicated in typical migraine susceptibility in the general Caucasian population, we also analyzed 82 independent pedigrees and a large case control group [36].
• Patients with congenital presynaptic failure, including two patients with episodic ataxia type 2 (EA-2) due to CACNA1A mutations, were studied with muscle biopsy, microelectrode studies, electron microscopy, DNA amplification, and sequencing [21].
• The disease-free survival curve of SCA6 was different from that of other SCAs and the mean age at onset for SCA6 was found to be later than that of the other types [37].
• METHODS: We screened 27 patients with SHM for mutations in the CACNA1A gene by a combination of single-strand conformational polymorphism analysis and sequence analysis [38].

References