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Sci Rep. 2018 Oct 24;8(1):15710. doi: 10.1038/s41598-018-34157-5.

Rapid degradation of progressive ankylosis protein (ANKH) in craniometaphyseal dysplasia.

Author information

1
Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, University of Connecticut Health, Farmington, CT, 06030, United States.
2
Center for Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, University of Connecticut Health, Farmington, CT, 06030, United States.
3
Program in Structural Biology, Sloan Kettering Institute, New York, NY, 10065, United States.
4
Department of Molecular Biophysics and Biochemistry, Department of Molecular, Cellular and Development Biology, Yale University, New Haven, CT, 06520, United States.
5
Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, University of Connecticut Health, Farmington, CT, 06030, United States. ipchen@uchc.edu.

Abstract

Mutations in the progressive ankylosis protein (NP_473368, human ANKH) cause craniometaphyseal dysplasia (CMD), characterized by progressive thickening of craniofacial bones and widened metaphyses in long bones. The pathogenesis of CMD remains largely unknown, and treatment for CMD is limited to surgical intervention. We have reported that knock-in mice (AnkKI/KI) carrying a F377del mutation in ANK (NM_020332, mouse ANK) replicate many features of CMD. Interestingly, ablation of the Ank gene in AnkKO/KO mice also leads to several CMD-like phenotypes. Mutations causing CMD led to decreased steady-state levels of ANK/ANKH protein due to rapid degradation. While wild type (wt) ANK was mostly associated with plasma membranes, endoplasmic reticulum (ER), Golgi apparatus and lysosomes, CMD-linked mutant ANK was aberrantly localized in cytoplasm. Inhibitors of proteasomal degradation significantly restored levels of overexpressed mutant ANK, whereas endogenous CMD-mutant ANK/ANKH levels were more strongly increased by inhibitors of lysosomal degradation. However, these inhibitors do not correct the mislocalization of mutant ANK. Co-expressing wt and CMD-mutant ANK in cells showed that CMD-mutant ANK does not negatively affect wt ANK expression and localization, and vice versa. In conclusion, our finding that CMD mutant ANK/ANKH protein is short-lived and mislocalized in cells may be part of the CMD pathogenesis.

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