The P/Q channel in human disease: Untangling the genetics and physiology

Abstract

Several neurological disorders are associated with mutations in CACNA1A, the gene which encodes the core subunit of P/Q calcium channels. Although there is overlap between the various phenotypes, particularly with respect to cerebellar involvement, different disorders are increasingly being associated with different aspects of P/Q-channel function. A preliminary genotype-phenotype relationship indicates that while almost any type of P/Q dysfunction can lead to progressive ataxia, mutations that increase channel function and those that remove arginines from S4 voltage sensors are most associated with migraine. In contrast, episodic ataxia and, to a lesser extent, epilepsy may be caused by mutations that decrease channel function. This dissection of channelopathies associated with P/Q channels is a case study of how rare experiments of nature may inform us about the different functions of widely expressed genes that play multiple roles in neurons. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim..