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Title: Characterisation of the voltage-gated potassium channel subunit, Kv8.2, and its role in inherited retinal disease
Author: Smith, K. E.
ISNI:       0000 0004 5363 6416
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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Cone Dystrophy with Supernormal Rod Electroretinogram (CDSRE) is an inherited retinal dystrophy leading to a progressive loss of vision. Mutations in the gene KCNV2, encoding a voltage-gated potassium (Kv) channel α-subunit, Kv8.2, have recently been linked to this condition. Kv8.2 belongs to a subfamily of modulatory α-subunits which do not form functional homomeric channels. This study aimed to characterise the properties of wild type Kv8.2 subunits and determine the functional effects of mutant Kv8.2 variants arising from KCNV2 mutations found in patients with CDSRE. A yeast two-hybrid approach was used to assess interactions between the tetramerisation (T1) domain of Kv8.2 with those of potential partner subunits. This approach revealed that the T1 domain of Kv8.2 interacted specifically with that of Kv2.1. Immunofluorescence revealed that the coexpression with Kv2.1 allowed Kv8.2 subunits to overcome their ER retention and form heteromeric Kv2.1/Kv8.2 channels at the plasma membrane. Whole cell patch-clamp electrophysiology was used to determine the biophysical properties of the Kv2.1/Kv8.2 heteromeric channels. In comparison to homomeric Kv2.1 channels, Kv2.1/Kv8.2 channels activated more quickly near the activation threshold, inactivated more slowly from both open and intermediate closed states, and had an accelerated rate of recovery from inactivation. Analysis of numerous Kv8.2 mutant subunits revealed several functional classes of missense mutations. Mutations at the T1 domain of Kv8.2 abolished the interaction with Kv2.1 resulting in an absence of Kv2.1/Kv8.2 heteromeric channels. Selected mutations in the pore region of Kv8.2 enabled the formation of heteromeric Kv2.1/Kv8.2 channels but abolished potassium conductance. Finally, a number of Kv8.2 mutant subunits were identified which may have influenced the assembly and/or trafficking of heteromeric Kv2.1/Kv8.2 channels. Together, these findings suggest that several different mutational mechanisms, which are dependent on the type of Kv8.2 mutation, all lead to a common phenotype of CDSRE.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available