Investigation of KCNK18 (TRESK) Genetic Variants in Migraine with and without Aura (S55.003)
Abstract
OBJECTIVE: The purposes of this study were to evaluate the frequency of KCNK18 genetic variants in a large dataset of patients affected by migraine with and without aura, and to evaluate in silico their functional relevance. BACKGROUND: Migraine is a chronic neurovascular disorder characterized by recurrent headache attacks that, in approximately 25% of cases, are associated with transient focal neurological symptoms (aura). Migraine with and without aura (MA and MO) have a strong genetic basis. Recently, a frameshift mutation (F139Wfsx24) in the KCNK18 gene (10q25.3) was reported in a large multigenerational MA pedigree. KCNK18 gene codes for TRESK, a member of the two-pore domain (K2P) family of potassium channels. The F139Wfsx24 mutation causes a complete loss of TRESK function, suggesting that TRESK dysfunction might play a possible role in migraine pathogenesis. DESIGN/METHODS: All three exons and intronic-exonic boundaries of the KCNK18 gene were sequenced in a large group of subjects, including 425 migraine patients (ICHD-II criteria; 255 MA, 170 MO) and 247 healthy controls. In silico analyses were performed using PolyPhen2 and SIFT programs. The clinical characteristics of migraineurs with gene mutations were examined. RESULTS: We identified five genetic variants (G10R, C110R, Y163Y, S231P, F372L) in the coding regions and one genetic variant (c352+24 C>T) in the intronic region of the KCNK18 gene in patients with either MA or MO. Three of these variants have been…
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