Open AccessMolecular pathogenesis of Spondylocheirodysplastic Ehlers‐Danlos syndrome caused by mutant ZIP13 proteins
Author(s) -
Bin BumHo,
Hojyo Shintaro,
Hosaka Toshiaki,
Bhin Jinhyuk,
Kano Hiroki,
Miyai Tomohiro,
Ikeda Mariko,
KimuraSomeya Tomomi,
Shirouzu Mikako,
Cho EunGyung,
Fukue Kazuhisa,
Kambe Taiho,
Ohashi Wakana,
Kim KyuHan,
Seo Juyeon,
Choi DongHwa,
Nam YeonJu,
Hwang Daehee,
Fukunaka Ayako,
Fujitani Yoshio,
Yokoyama Shigeyuki,
SupertiFurga Andrea,
Ikegawa Shiro,
Lee Tae Ryong,
Fukada Toshiyuki
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201303809
Subject(s) - mutant , pathogenesis , ehlers–danlos syndrome , proteasome , protein degradation , mutant protein , ubiquitin , microbiology and biotechnology , chemistry , biology , biochemistry , gene , medicine , immunology , pathology
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.