title: Genetic and functional analysis of TBK1 variants in Korean patients with sporadic amyotrophic lateral sclerosis.
abstract: The TANK-binding kinase 1 (TBK1) gene has recently been identified as a novel causative gene of amyotrophic lateral sclerosis (ALS). This study aims to determine the frequency and spectrum of TBK1 variants and their functional implications in Korean patients with sporadic ALS (sALS). TBK1 sequences were analyzed in 129 consecutive patients with sALS using either multigene panel or exome sequencing. One frameshift (c.1414delA) and 3 missense variants of uncertain significance in TBK1 were found in 4 patients each. In vitro functional studies revealed that the c.1414delA (p.Ile472Serfs*8) variant was associated with reduced mRNA expression of TBK1. Moreover, protein expression of this variant in patient-derived fibroblasts disrupted binding to autophagy adapter proteins and inhibited the function of TBK1 in HEK293T cells. In contrast, the 3 other missense variants of uncertain significance showed normal mRNA expression and no abnormalities in protein function. Based on these findings, the frequency of pathogenic TBK1 variants in Korean sALS patients was estimated to be 0.8% (1/129). In conclusion, pathogenic variants in TBK1 are rare but could be responsible for sALS in a small number of Korean patients.
authors.affiliation: Green Cross Genome, Yongin, Republic of Korea.
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Kim
authors.affiliation: Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea; Cell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea.
authors.forename: Ki-Wook
authors.initials: KW
authors.lastname: Oh
authors.affiliation: Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea; Cell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea.
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Noh
authors.affiliation: Cell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea.
authors.forename: Minyeop
authors.initials: M
authors.lastname: Nahm
authors.affiliation: Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea; Cell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea.
authors.forename: Jinseok
authors.initials: J
authors.lastname: Park
authors.affiliation: Cell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea.
authors.forename: Su Min
authors.initials: SM
authors.lastname: Lim
authors.affiliation: Green Cross Genome, Yongin, Republic of Korea.
authors.forename: Ja-Hyun
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Green Cross Genome, Yongin, Republic of Korea.
authors.forename: Eun-Hae
authors.initials: EH
authors.lastname: Cho
authors.affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: changski@skku.edu.
authors.forename: Chang-Seok
authors.initials: CS
authors.lastname: Ki
authors.affiliation: Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seungbok
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea; Cell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea. Electronic address: kimsh1@hanyang.ac.kr.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D005964:Glucosyltransferases / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007723:Korea; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D020539:Sequence Analysis, Protein; D055815:Young Adult
chemical_list: D001426:Bacterial Proteins; D012333:RNA, Messenger; C117828:ExoM protein, Sinorhizobium meliloti; D005964:Glucosyltransferases; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human
keywords: Amyotrophic lateral sclerosis; Gene; Pathogenic; TBK1; Variant