Rajakulendran, S.; (2010) Genetic and molecular expression studies of ion channel disorders of Kv1.1 and Cav2.1. Doctoral thesis , UCL (University College London).

Abstract

Mutations in the shaker potassium channel (KV1.1) gene KCNA1 are associated with episodic ataxia type 1 (EA1) while mutations in the CACNA1A gene which encodes the CaV2.1 calcium channel underlie episodic ataxia type 2 (EA2). Both disorders exhibit dominant inheritance and are characterised clinically by paroxysmal attacks of cerebellar dysfunction. This thesis explores the relationship between six new mutations in KCNA1, EA1 phenotype and functional consequences of expressed mutations. Expression of all six mutations demonstrated a loss of function. There was an imperfect correlation between phenotypic severity of EA1 and in vitro electrophysiology with respect to mutations. Supporting this indirect relationship, this thesis reports that non-genetic factors influence the phenotypic outcome of EA1 in monozygotic twins. In recognition of the importance of studying mutations in physiologically relevant conditions, this thesis describes the use of a lentivirus as a tool for studying the effects of KCNA1 mutations in neurons. A number of individuals with clinical EA2 do not harbour point mutations in CACNA1A. A screen for rearrangements in eighteen such individuals identified deletions of at least one exon of CACNA1A in three patients with EA2 suggesting that such large deletions are an important cause of EA2. This thesis tested the hypothesis that genetic variation in CACNA1A conferring a loss of CaV2.1 function is associated with the syndrome of episodic ataxia with epilepsy. CACNA1A was sequenced in 17 individuals with a clinical phenotype of EA accompanied by epilepsy and/or epileptiform EEGs. The functional impact of newly identified missense mutations and all non-synonymous coding variants (nCVs) in the 17 individuals was determined using voltage clamp experiments. Twelve of the 17 patients had genetic variants which reduced CaV2.1 function. These findings suggest that variations in CACNA1A which result in varying degrees of loss of channel function are likely to predispose individuals to episodic ataxia with epilepsy.

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