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Molecular pathogenesis of spondylocheirodysplastic Ehlers-Danlos syndrome caused by mutant ZIP13 proteins.

EMBO molecular medicine (2014-07-11)
Bum-Ho Bin, Shintaro Hojyo, Toshiaki Hosaka, Jinhyuk Bhin, Hiroki Kano, Tomohiro Miyai, Mariko Ikeda, Tomomi Kimura-Someya, Mikako Shirouzu, Eun-Gyung Cho, Kazuhisa Fukue, Taiho Kambe, Wakana Ohashi, Kyu-Han Kim, Juyeon Seo, Dong-Hwa Choi, Yeon-Ju Nam, Daehee Hwang, Ayako Fukunaka, Yoshio Fujitani, Shigeyuki Yokoyama, Andrea Superti-Furga, Shiro Ikegawa, Tae Ryong Lee, Toshiyuki Fukada
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.

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