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

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


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.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Diseases, Developmental / etiology*
  • Bone Diseases, Developmental / genetics
  • Cells, Cultured
  • Craniofacial Abnormalities / etiology*
  • Craniofacial Abnormalities / genetics
  • Humans
  • Hyperostosis / etiology*
  • Hyperostosis / genetics
  • Hypertelorism / etiology*
  • Hypertelorism / genetics
  • Mice
  • Mutation
  • Phosphate Transport Proteins / genetics
  • Phosphate Transport Proteins / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Stability
  • Rats
  • Saccharomyces cerevisiae
  • Ubiquitination


  • ANKH protein, human
  • Phosphate Transport Proteins
  • Proteasome Endopeptidase Complex

Supplementary concepts

  • Schwartz-Lelek syndrome