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Genetic and molecular studies of skeletal muscle channelopathies

Durran, SCM; (2016) Genetic and molecular studies of skeletal muscle channelopathies. Doctoral thesis , UCL (University College London). Green open access

Durran_Siobhan Durran Thesis with corrections.pdf

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This thesis investigates the genetic and molecular aspects of the skeletal muscle channelopathies, in particular periodic paralysis. A genetic study was conducted to identify causative mutations in a cohort of patients who did not have a genetic diagnosis following routine diagnostic screening. Through screening of the coding regions of SCN4A 9 mutations were identified, 6 of which were novel. Additionally, exome sequencing in a PMC family identified 10 variants in 7 genes, although only three genes of interest: RYR-1, AGRN and COL6A3. However, further work is needed to confirm the variants found. Two SCN4A mutations identified in this thesis were studied in vitro using twoelectrode voltage clamp and patch clamp in Xenopus laevis oocytes and HEK-293 cells, respectively. D1420G is associated with a Hypo PP phenotype and is located within the S3 segment of DIV. No Hypo PP mutation has been associated with this region of the channel. D1420G was found to produce a gating pore current which is activated by negative voltages. This is the first Hypo PP mutation outside of the S4 voltage sensor to produce a gating pore current and support the notion that D1420G is a pathogenic mutation. R222Q was identified in a patient showing a myotonic phenotype. R222Q affects the S4 R2 gating charge of DI. A known Hypokalemic Periodic Paralysis mutation, R222W, affects the same residue. Both R222 mutations were compared in order to determine how two mutations affecting the same residue can cause different phenotypes. R222Q was found to cause a 16 mV hyperpolarizing shift in the voltage dependence of channel activation, which is consistent with a myotonic phenotype, whilst R222W had no effect. Both mutations were found to produce a gating pore current. This is the first time a myotonia related mutation has been found to cause a gating pore current.

Type: Thesis (Doctoral)
Title: Genetic and molecular studies of skeletal muscle channelopathies
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
URI: http://discovery.ucl.ac.uk/id/eprint/1485744
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