Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM

Mutations in the brain specific P/Q type Ca2+ channel alpha1 subunit gene, CACNA1A, have been identified in three clinically distinct disorders, viz. episodic ataxia type 2 (EA-2), familial hemiplegic migraine (FHM) and spino cerebellar ataxia 6 (SCA6). For individuals with EA-2, the mutations descri bed thus far are presumed to result in a truncated protein product. Several different missense mutations have been identified in patients with FHM. At least two of these mutations have been identified on two different chromos ome 19p13 haplotypes and thus represent recurrent mutations. In the present study, we have screened several individuals for mutations in all 47 exons in the CACNA1A gene by single-strand conformation analysis. We have charact erised a novel missense mutation, G5260A, in exon 32 in a family segregatin g for EA-2. The consequence of this mutation is an amino acid substitution at a highly conserved position within the CACNA1A gene. This represents the first point mutation not resulting in a proposed truncated protein. Furthe rmore, this mutation has been detected in a family member with mild clinica l signs including only migraine. Additionally, a second previously identifi ed recurrent mutation, C2272T, in exon 16 has been discovered in a patient with FHM.