title: CLEC4C p.K210del variant causes impaired cell surface transport in plasmacytoid dendritic cells of amyotrophic lateral sclerosis.
abstract: The type II C-type lectin CLEC4C is a transmembrane protein selectively expressed on plasmacytoid dendritic cells (PDCs). Although its mechanism of action remains unclear, triggering of the extracellular C-terminal C-type carbohydrate recognition region of CLEC4C regulates the secretion of proinflammatory cytokines and type I IFNs in PDCs. Applying whole-exome sequencing in a patient with juvenile amyotrophic lateral sclerosis (ALS) and both healthy parents, we identified a de novo CLEC4C variant (c.629_631delAGA; p.Lys210del). In this study, we report that the deletion of a lysine residue at the extracellular region of CLEC4C yields a C-terminal dilysine motif that results in endoplasmic reticulum (ER) retention of the protein in transfected HeLa and Jurkat T lymphoma cell models. As a consequence, a decrease in the surface expression of CLEC4C and the ER localization of the mutant construct were observed. Furthermore, depletion of the cell surface CLEC4C level was also observed in the patient PDCs, further suggesting that the variant p.Lys210del CLEC4C may contribute to juvenile ALS susceptibility.
authors.affiliation: Department of Translational Medicine, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.|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: Young-Eun
authors.initials: YE
authors.lastname: Kim
authors.affiliation: Department of Neurology, Sheikh Khalifa Specialty Hospital, Ras Al Khaimah, United Arab Emirates.
authors.forename: Won Jun
authors.initials: WJ
authors.lastname: Choi
authors.affiliation: Department of Neurology, College of Medicine, Hanyang University, 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: Cell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea.
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Noh
authors.affiliation: Department of Pharmacology, School of Medicine, CHA University, CHA Bio Complex, Seongnam, Republic of Korea.
authors.forename: Min-Soo
authors.initials: MS
authors.lastname: Kwon
authors.affiliation: Cell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea.
authors.forename: Minyeop
authors.initials: M
authors.lastname: Nahm
authors.affiliation: Epigenomics Research Center Genome Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Namshin
authors.initials: N
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Chang-Seok
authors.initials: CS
authors.lastname: Ki
authors.affiliation: Department of Translational Medicine, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.|Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea.|Cell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D021381:Protein Transport / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics*; D055815:Young Adult
chemical_list: C443299:CLEC4C protein, human; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic
keywords: C-type lectin; ER retention; Gerotarget; amyotrophic lateral sclerosis; dilysine motif; whole-exome sequencing