Servet Göncü, BeyzaYücesan, EmrahAslanger, Ayça DilrubaÖzgül, CemilHasanoğlu, SevdeYeşil Sayın, Gözde2021-02-092021-02-092020-12-01http://hdl.handle.net/20.500.12645/28404Introduction: KCNMA1 encodes, the alpha subunit of the voltage, and calcium-sensitive potassium channel, predominantly expressed in the central nervous system. Therefore abnormal function in this gene may occur neurological conditions.Materials and Methods: We report 15-year-old patient who was born at term with healthy conditions. Motor signals were delayed, and also seizures started at the age of 18 months. EEG revealed generalized spike-wave activities. Brain MRI performed, atrophy of the cerebellum was detected. Recent clinical examination; contractures on the large joints, and dyskinetic tremor. Whole exome sequencing (WES) was performed and in-slico analyses were conducted. MCF7 and 293T cells transfected with either wild-type or mutant expression vectors. Cellular distribution was determined by immunofluorescence. Functional analysis was performed using electrophysiological approach based on whole-cell patch-clamp.Results: WES revealed homozygous variation (NM_001161352.1:c.1372C>T, p.Arg458Ter). The variant was not observed in publicly available or in-house databases. Immunofluorescent staining revealed that novel variant is not interfering with the synthesis of KCNMA1 however mutation exhibit dominant-negative effect on cell viability when compared to wild-type. 293T and MCF7 cells transfected with homozygous p.Arg458Ter mutation showed markedly increased KCNMA1 currents compared to controls on patch-clamp recording, and these data support loss-of-function effect of all KCNMA1 mutants.Conclusions: Herein we report a 15-year old boy who has neurological conditions. A novel homozygous stop-gain mutation detected by WES and confirmed by conventional sequencing. Afterward, functional characterization was conducted using two step-approach, immunostaining to detect subcellular effect of the variation and patch-clamp to detect a difference between mutant vs. wild-type of the protein. Homozygous mutation was considered as causative for this clinical condition. This study was supported by Bezmialem Vakif University, Scientific Research Projects Unit, Project No:2.2019/7.Yücesan E., Servet Göncü B., Aslanger A. D. , Özgül C., Hasanoğlu S., Yeşil Sayın G., -Identification and functional characterization of a novel homozygous mutation in KCNMA1 encoding voltage and calcium sensitive potassium channel is associated with dyskinesia, epilepsy, intellectual disability, cerebellar and corticospinal tract atrophy-, Conference of the European-Society-of-Human-Genetics (ESHG), 6 - 09 Eylül 2020, cilt.28, ss.204-205Conference Paper