새로운 KCNQ4 돌연 변이의 발견 및 난청 유형 분석

학위논문 (박사)-- 서울대학교 대학원 의과대학 의학과, 2017. 8. 오승하.KCNQ4 mutations lead to autosomal dominant non-syndromic, and typically progressive and high-frequency, hearing loss (HL). In this report, I identified two novel KCNQ4 mutations, namely p.R331Q and p.811_816del, in two different families. One mutation in the C-terminal region was associated with low- to mid-frequency HL and the other mutation, located in the P-loop, was associated with high frequency HL. Although I did not observe a difference in the subcellular localization of the KCNQ4 mutants p.R331Q and c.811_816del, c.811_816del protein expression was significantly decreased compared with that of wild-type KCNQ4 (KCNQ4WT) and the p.R331Q mutant. The potassium currents were significantly decreased in both the p.R331Q and c.811_816del mutants compared with KCNQ4WT, indicative of the pathogenic potential of the two variants. Based on electrophysiological data, p.R331Q and c.811_816del KCNQ4 channels showed loss of function and a dominant-negative effect when combined with functional KCNQ4WT channels. The heteromeric mutant channels assembled with WT were activated by a KCNQ4 activator (retigabine), and the degree of rescue by retigabine was stronger in the p.R331Q heteromer than in the c.811_816del heteromer. This study reports a C-terminal tail variant among KCNQ4 mutants for the first time, and broadens the audiologic phenotypic spectrum from high frequency sensorineural HL to include low- to mid-frequency sensorineural HL.Introduction 1 Materials and Methods 2 Results 9 Discussion 16 References 20 Figures 24 Abstract (Korean) 33Docto