Clusters of non-truncating mutations of P/Q type Ca2+ channel subunit Ca(v)2.1 causing episodic ataxia 2

Episodic ataxia type 2 (EA2) is mostly due to loss of function mutations that truncate or severely disrupt the pore forming (Cav2.1) subunit of P/Q type Ca2+ channels, coded by the CACNA1A gene. Gain of function missense mutations of the same gene are responsible for familial hemiplegic migraine. In a few cases, EA2 is due to mutations that do not truncate or disrupt the Cav2.1 subunit. Screening for CACNA1A gene mutations was carried out for 27 patients with either typical EA2 or cerebellar ataxia of no known genetic type. Five new Cav2.1 non-truncating/disrupting mutations were detected. From almost doubling the number of these mutations, it clearly emerges that they have a preferential location in specific protein regions, namely S5–S6 linkers and their borders. Their associated clinical phenotype is comparable with that reported for carriers of truncating/disrupting mutations, but data suggest a possible difference in age at onset and frequency of mental retardation. The results show that EA2 mutations that do not truncate or disrupt the Cav2.1 subunit are not as rare as previously thought. Their associated phenotype might be less severe than that of truncating/disrupting mutations. They are clustered in highly conserved protein regions which may be particularly vulnerable to amino acid changes and are likely to have a critical role in the channel gating activity