Molecular pathogenesis of Spondylocheirodysplastic Ehlers‐Danlos syndrome caused by mutant ZIP13 proteins. Issue 8 (9th July 2014)

• Record Type: Journal Article
• Authors: Bin, Bum‐Ho; Hojyo, Shintaro; Hosaka, Toshiaki; Bhin, Jinhyuk; Kano, Hiroki; Miyai, Tomohiro; Ikeda, Mariko; Kimura‐Someya, Tomomi; Shirouzu, Mikako; Cho, Eun‐Gyung; Fukue, Kazuhisa; Kambe, Taiho; Ohashi, Wakana; Kim, Kyu‐Han; Seo, Juyeon; Choi, Dong‐Hwa; Nam, Yeon‐Ju; Hwang, Daehee; Fukunaka, Ayako; Fujitani, Yoshio; Yokoyama, Shigeyuki; Superti‐Furga, Andrea; Ikegawa, Shiro; Lee, Tae Ryong; Fukada, Toshiyuki
• Is Part Of: EMBO molecular medicine. Volume 6:Issue 8(2014:Aug.)
• Page Start: 1028
• Page End: 1042
• Publication Date: 2014-07-09
• Subjects: Proteasome -- SCD‐EDS -- VCP -- zinc transporter -- ZIP13; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201303809
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: The Spondylocheirodysplastic Ehlers‐Danlos syndrome pathogenic ZIP13 mutants are degraded by the ubiquitin‐proteasome pathway. Inhibition of this pathway restores ZIP13 levels with consequent improvement of intracellular Zn homeostasis. The Spondylocheirodysplastic Ehlers‐Danlos syndrome pathogenic ZIP13 mutant proteins: ZIP13G64D and ZIP13ΔFLA, are degraded by the ubiquitin‐proteasome pathway. Valosin‐containing protein (VCP) is involved in the degradation of the pathogenic mutant ZIP13 proteins. The reduced expression levels of the ZIP13 mutant proteins are rescued by inhibition of the degradation pathways, resulting in improved intracellular zinc homeostasis. Abstract : The Spondylocheirodysplastic Ehlers‐Danlos syndrome pathogenic ZIP13 mutants are degraded by the ubiquitin‐proteasome pathway. Inhibition of this pathway restores ZIP13 levels with consequent improvement of intracellular Zn homeostasis.