Episodic Ataxia Type 2 (EA2) and Spinocerebellar Ataxia Type 6 (SCA6) Due to CAG Repeat Expansion in the CACNA1A Gene on Chromosome 19p

Point mutations of the CACNA1A gene coding for the α1A voltage-dependent calcium channel subunit are responsible for familial hemiplegic migraine (FHM) and episodic ataxia type 2 (EA2). In addition, expansions of the CAG repeat motif at the 3′ end of the gene, smaller than those responsible for dyna...

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Bibliographic Details
Published in:Human molecular genetics 1997-10, Vol.6 (11), p.1973-1978
Main Authors: Jodice, Carla, Mantuano, Elide, Veneziano, Liana, Trettel, Flavia, Sabbadini, Guglielmo, Calandriello, Luigi, Francia, Ada, Spadaro, Maria, Pierelli, Francesco, Salvi, Fabrizio, Ophoff, Roel A., Frants, Rune R., Frontali, Marina
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Aged, 80 and over
Alleles
Biological and medical sciences
Calcium Channels - genetics
Cerebellar Ataxia - genetics
Chromosomes, Human, Pair 19
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Exons
Female
Humans
Introns
Male
Medical sciences
Middle Aged
Mutation
Neurology
Pedigree
Phenotype
Spinocerebellar Degenerations - genetics
Trinucleotide Repeats
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Summary:Point mutations of the CACNA1A gene coding for the α1A voltage-dependent calcium channel subunit are responsible for familial hemiplegic migraine (FHM) and episodic ataxia type 2 (EA2). In addition, expansions of the CAG repeat motif at the 3′ end of the gene, smaller than those responsible for dynamic mutation disorders, were found in patients with a progressive spinocere-bellar ataxia, named SCA6. In the present work, the analysis of two new families with small CAG expansions of the CACNA1A gene is presented. In one family, with a clinical diagnosis of EA2, a CAG23 repeat allele segregated 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 the second family, initially classified as autosomal dominant cerebellar ataxia of unknown type, an inter-generational allele size change showed that a CAG20 allele was associated with an EA2 phenotype and a CAG25 allele with progressive cerebellar ataxia. These results show that EA2 and SCA6 are the same disorder with a high pheno-typic variability, at least partly related to the number of repeats, and suggest that the small expansions may not be as stable as previously reported. A refinement of the coding and intron-exon junction sequences of the CACNA1A gene is also provided.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/6.11.1973