These authors contributed equally to this work.
Molecular pathogenesis of Spondylocheirodysplastic Ehlers-Danlos syndrome caused by mutant ZIP13 proteins
Version of Record online: 9 JUL 2014
© 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 6, Issue 8, pages 1028–1042, August 2014
How to Cite
EMBO Mol Med (2014) 6:1028–1042
- Issue online: 1 AUG 2014
- Version of Record online: 9 JUL 2014
- Manuscript Accepted: 27 MAY 2014
- Manuscript Revised: 26 MAY 2014
- Manuscript Received: 29 DEC 2013
- Japan Society for the Promotion of Science (JSPS)
- Life Science Foundation of Japan
- Japan Osteoporosis Foundation
- Targeted Proteins Research Program
- Platform for Drug Discovery, Informatics, and Structural Life Science
- Ministry of Education, Culture, Sports, Science, and Technology
- VCP ;
- zinc transporter;
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: ZIP13G64D, in which Gly at amino acid position 64 is replaced by Asp, and ZIP13ΔFLA, which contains a deletion of Phe-Leu-Ala. We demonstrated that both the ZIP13G64D and ZIP13ΔFLA 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.
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.