CACNA1A Mutations Research Articles

Missense CACNA1A mutation causing episodic ataxia type 2.

To characterize the nature of CACNA1A mutation in a previously unreported family with episodic ataxia type 2 (EA2) and to better delineate EA2 clinical features. Episodic ataxia type 2 is an autosomal dominant disorder characterized by the recurrence of acetazolamide-responsive spells of cerebellar ataxia, usually starting during childhood or adolescence. The mutated gene, CACNA1A, is located on chromosome 19 and encodes the alpha1A subunit voltage-dependent calcium channel. So far, most CACNA1A mutations detected in patients with EA2 have led to a truncated CACNA1A protein, whereas missense mutations cause familial hemiplegic migraine. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. A CACNA1A missense mutation, Glu 1757 Lys, was identified. It was absent in 200 control chromosomes. It is predicted to result in an amino acid substitution at a highly phylogenetically conserved position, within a domain that plays a major role in the function of the channel. The Glu 1757 Lys missense mutation is likely to be pathogenic, causing episodic ataxia within a family whose phenotype is indistinguishable from EA2 except for a slightly later age of onset. These data strongly suggest that additional work is needed to fully establish genotype/phenotype correlations for CACNA1A mutations.

Genetics of familial hemiplegic migraine

Familial hemiplegic migraine is an autosomal dominant form of migraine with aura, characterized by the occurrence of a motor deficit during the aura. In 20% of families, permanent cerebellar signs (ataxia or nystagmus) are observed. This condition is genetically heterogeneous. A first gene, CACNA1A, located on chromosome 19 and encoding the main subunit of P/Q type neuronal calcium channel, is implicated in 50% of unselected families and in all families with cerebellar symptoms. Thirteen distinct point mutations of CACNA1A have been identified so far in familial and sporadic cases. A second yet unidentified gene located on chromosome 1 is implicated in 20% of the families. One or more other genes are still to be mapped. Various approaches have been used to understand the mechanisms leading from the CACNA1A mutations to hemiplegic migraine, including in vitro electrophysiological studies as well as detailed analysis of the CACNA1A mutant mice tottering and leaner.

CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy.

Familial hemiplegic migraine is caused by CACNA1A missense mutations in 50% of families, including all families with cerebellar ataxia. A patient with healthy parents, who experienced prolonged attacks of migraine with hemiplegia, coma, and seizures, is reported. The patient also had mental retardation, permanent cerebellar ataxia with cerebellar atrophy, and right-sided brain atrophy. This patient carried a de novo Tyr 1385 Cys mutation in the CACNA1A gene and illustrates a novel phenotype associated with CACNA1A mutations.

A novel nonsense mutation in CACNA1A causes episodic ataxia and hemiplegia.

To identify the disease-causing mutation and to characterize penetrance and phenotypic variability in a large pedigree with episodic ataxia type 2 (EA-2) previously linked to chromosome 19. Mutations in the CACNA1A gene on chromosome 19 encoding a calcium channel subunit cause EA-2, which is characterized by recurrent attacks of imbalance with interictal eye movement abnormalities. The authors used single-strand conformation polymorphism (SSCP) analysis to screen for point mutations, and direct sequencing to identify mutations in CACNA1A. Allele-specific oligonucleotides were designed to detect the presence of the diseased allele in members of their pedigree as well as in normal control subjects. Reassessment of members of the pedigree revealed two notable clinical features. Diffuse weakness during attacks of ataxia was a prominent complaint. Two affected individuals had had episodic hemiplegia, one with typical migraine headaches. SSCP analysis revealed aberrant bands in exon 29 in affected members but not in normal control subjects. Direct sequencing of exon 29 identified a C-to-T change at position 4914 of the coding sequence of CACNA1A, predicting an early stop code at codon 1547. Two asymptomatic mutation carriers demonstrated the incomplete penetrance of this mutation. A nonsense mutation in CACNA1A causes episodic ataxia and complaint of weakness, and may be associated with hemiplegia.

July 13 Highlights

Hedera et al. (p. 44) describe the phenotype of hereditary spastic paraplegia (HSP) linked to chromosome 8q23-24. Other than increased severity, no clinical features distinguished the family they describe from those with autosomal dominant HSP linked to other chromosomes. The authors question whether the multiple genes responsible for these clinically indistinguishable disorders involve a common biochemical cascade. Mitochondrial disturbance, postulated to be a common factor of HSP, is not a feature of the new gene. Martinez-Murillo et al. (p. 50) characterize a new and apparently common gene locus for recessive familial spastic paraparesis linked to chromosome 15q. In their accompanying editorial, Figlewicz and Bird (p. 5) review the genetics of HSP and highlight the critical issues that must be settled. ♦ Three articles and the editorial by Tournier-Lasserve (p. 3) relate to CACNA1A mutations. Jen et al. (p. 34) describe a nonsense mutation …

High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2.

To characterize the nature of CACNA1A mutations in episodic ataxia type 2 (EA2), to search for mutations in sporadic cases, and to delineate better the clinical spectrum. EA2 is an autosomal dominant disorder characterized by recurrent acetazolamide-responsive attacks of cerebellar ataxia. The mutated gene, CACNA1A, located on chromosome 19, encodes the alpha1A subunit of a voltage-dependent calcium channel. So far, only three CACNA1A mutations have been identified-in two EA2 families and in one sporadic case. These three mutations disrupted the reading frame and led to truncated proteins. Interestingly, distinct types of CACNA1A mutations have been identified in familial hemiplegic migraine (missense mutations) and spinocerebellar ataxia type 6 (SCA-6) progressive cerebellar ataxia (expanded CAG repeats). However, except for SCA-6, these genotype-phenotype correlations relied on the analysis of very few families. To characterize CACNA1A mutations, eight familial and seven sporadic EA2 patients were selected. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. In addition, the length of the CAG repeat has been determined in all patients. Seven new mutations were detected in four multiple case families and three sporadic cases. Six of them lead most likely to truncated or aberrant proteins. CAG repeat sizes were in the normal range. These data clearly establish the specificity of EA2 mutations compared with SCA-6 and familial hemiplegic migraine. Detailed clinical analysis of the mutation carriers showed the highly variable penetrance and expression of this disorder: Several of the carriers did not show any clinical symptom; others displayed atypical or permanent neurologic symptoms (such as recurrent, transient diplopia or severe, permanent, and isolated cerebellar ataxia).

Calcium channelopathies in the central nervous system

The recent discovery that familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6 are allelic disorders caused by different mutations in CACNA1A, a calcium-channel-encoding gene, adds to a growing list of channelopathies causing paroxysmal neurologic disturbance and progressive neurodegeneration. Calcium channelopathies in the central nervous system provide a model to study the important roles that calcium channels play in neuronal function.

Recurrence of the T666M Calcium Channel CACNA1A Gene Mutation in Familial Hemiplegic Migraine with Progressive Cerebellar Ataxia

Familial hemiplegic migraine (HM) is an autosomal dominant migraine with aura. In 20% of HM families, HM is associated with a mild permanent cerebellar ataxia (PCA). The CACNA1A gene encoding the alpha1A subunit of P/Q-type voltage-gated calcium channels is involved in 50% of unselected HM families and in all families with HM/PCA. Four CACNA1A missense mutations have been identified in HM: two in pure HM and two in HM/PCA. Different CACNA1A mutations have been identified in other autosomal dominant conditions: mutations leading to a truncated protein in episodic ataxia type 2 (EA2), small expansions of a CAG trinucleotide in spinocerebellar ataxia type 6 and also in three families with EA2 features, and, finally, a missense mutation in a single family suffering from episodic ataxia and severe progressive PCA. We screened 16 families and 3 nonfamilial case patients affected by HM/PCA for specific CACNA1A mutations and found nine families and one nonfamilial case with the same T666M mutation, one new mutation (D715E) in one family, and no CAG repeat expansion. Both T666M and D715E substitutions were absent in 12 probands belonging to pure HM families whose disease appears to be linked to CACNA1A. Finally, haplotyping with neighboring markers suggested that T666M arose through recurrent mutational events. These data could indicate that the PCA observed in 20% of HM families results from specific pathophysiologic mechanisms.

Familial migraine with vertigo: no mutations found in CACNA1A.

We searched for mutations in the voltage-gated calcium channel gene, CACNA1A, in nine propositi of families with migraine headaches and episodic vertigo inherited in an autosomal dominant pattern. All 47 exons and flanking introns in CACNA1A were subjected to single-strand conformation polymorphism analysis of polymerase chain reaction-amplified genomic DNA. Exons with aberrantly migrating fragments were sequenced using standard techniques. We also determined the CAG repeat length at the 3' end of CACNA1A. Several polymorphisms were found but no mutations identified in any of the 47 exons of the 9 patients. No index-case had a CAG repeat length greater than 13 (normal <17). Mutations in CACNA1A are not common in families with migraine headaches and episodic vertigo. Other ion channel genes expressed in the brain and inner ear remain candidate genes.