title: Molecular pathogenesis of spondylocheirodysplastic Ehlers-Danlos syndrome caused by mutant ZIP13 proteins.
abstract: The zinc transporter protein ZIP13 plays critical roles in bone, tooth, and connective tissue development, and its dysfunction is responsible for the spondylocheirodysplastic form of Ehlers-Danlos syndrome (SCD-EDS, OMIM 612350). Here, we report the molecular pathogenic mechanism of SCD-EDS caused by two different mutant ZIP13 proteins found in human patients: ZIP13(G64D), in which Gly at amino acid position 64 is replaced by Asp, and ZIP13(ΔFLA), which contains a deletion of Phe-Leu-Ala. We demonstrated that both the ZIP13(G64D) and ZIP13(ΔFLA) protein levels are decreased by degradation via the valosin-containing protein (VCP)-linked ubiquitin proteasome pathway. The inhibition of degradation pathways rescued the protein expression levels, resulting in improved intracellular Zn homeostasis. Our findings uncover the pathogenic mechanisms elicited by mutant ZIP13 proteins. Further elucidation of these degradation processes may lead to novel therapeutic targets for SCD-EDS.
authors.affiliation: Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry Showa University, Shinagawa, Japan.
authors.forename: Bum-Ho
authors.initials: BH
authors.lastname: Bin
authors.affiliation: Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan Deutsches Rheuma-Forschungszentrum, Berlin, Osteoimmunology, Berlin, Germany.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Hojyo
authors.affiliation: RIKEN Systems and Structural Biology Center, Yokohama, Japan Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hosaka
authors.affiliation: Department of Chemical Engineering, POSTECH, Pohang, Republic of Korea.
authors.forename: Jinhyuk
authors.initials: J
authors.lastname: Bhin
authors.affiliation: Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kano
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan Laboratory for Immune Regeneration, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Miyai
authors.affiliation: RIKEN Systems and Structural Biology Center, Yokohama, Japan Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: RIKEN Systems and Structural Biology Center, Yokohama, Japan Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kimura-Someya
authors.affiliation: RIKEN Systems and Structural Biology Center, Yokohama, Japan Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Japan.
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.affiliation: Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea.
authors.forename: Eun-Gyung
authors.initials: EG
authors.lastname: Cho
authors.affiliation: Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Fukue
authors.affiliation: Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Taiho
authors.initials: T
authors.lastname: Kambe
authors.affiliation: Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Wakana
authors.initials: W
authors.lastname: Ohashi
authors.affiliation: Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea.
authors.forename: Kyu-Han
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea.
authors.forename: Juyeon
authors.initials: J
authors.lastname: Seo
authors.affiliation: Gyeonggi Bio Center, Gyeonggi Institute of Science & Technology Promotion, Suwon, Republic of Korea.
authors.forename: Dong-Hwa
authors.initials: DH
authors.lastname: Choi
authors.affiliation: Gyeonggi Bio Center, Gyeonggi Institute of Science & Technology Promotion, Suwon, Republic of Korea.
authors.forename: Yeon-Ju
authors.initials: YJ
authors.lastname: Nam
authors.affiliation: Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Daegu, Republic of Korea.
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.affiliation: Center for Beta-Cell Biology and Regeneration, Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Fukunaka
authors.affiliation: Center for Beta-Cell Biology and Regeneration, Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujitani
authors.affiliation: RIKEN Systems and Structural Biology Center, Yokohama, Japan RIKEN Structural Biology Laboratory, Yokohama, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.affiliation: Department of Pediatrics, Centre Hospitalier Universitaire Vaudois University of Lausanne, Lausanne, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.affiliation: Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.affiliation: Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea trlee@amorepacific.com fukada@rcai.riken.jp.
authors.forename: Tae Ryong
authors.initials: TR
authors.lastname: Lee
authors.affiliation: Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry Showa University, Shinagawa, Japan Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan trlee@amorepacific.com fukada@rcai.riken.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fukada
mesh_terms: D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D017384:Sequence Deletion; D025801:Ubiquitin / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D050505:Mutant Proteins; C521172:SLC39A13 protein, human; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D015032:Zinc
keywords: Proteasome; SCD‐EDS; VCP; ZIP13; zinc transporter