Mutations in ADNP affect expression and subcellular localization of the protein

Cell Cycle. 2018;17(9):1068-1075. doi: 10.1080/15384101.2018.1471313. Epub 2018 Jul 17.


Truncating de novo mutations in ADNP have been identified in patients with the Helsmoortel-Van der Aa syndrome. However correlations between the distinct mutations and their impact on the protein have not been studied before. Here we report the effect of mutations in ADNP by examining the expression and subcellular localization of GFP-tagged mutant transcripts in transfected HEK293T cells. ADNP encloses a bipartite nuclear localization signal and we found mutations therein to stall the mutant protein within the cytoplasm. Using immunocytochemistry, we could demonstrate colocalization of wild-type ADNP with heterochromatin. We found mutations presenting a pattern based on the genetic position. For certain mutant proteins enrichment at pericentromeric heterochromatin seems partially lost. Finally, N-terminal truncated ADNP mutants are routed towards cytosolic proteasomal degradation and rescued with the proteasome inhibitor MG132. Our results suggest a correlation between the position of the mutations across the protein, its stability and subcellular localization.

Keywords: ADNP; NLS; Subcellular expression; nuclear localization; proteolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autism Spectrum Disorder / genetics*
  • Body Dysmorphic Disorders / genetics*
  • Cell Nucleus / metabolism*
  • Codon, Nonsense
  • Cohort Studies
  • Cytoplasm / metabolism*
  • HEK293 Cells
  • Heterochromatin / metabolism
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism*
  • Humans
  • Intellectual Disability / genetics*
  • Muscle Hypotonia / genetics*
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Localization Signals
  • Proteasome Endopeptidase Complex / metabolism
  • Syndrome
  • Transfection


  • ADNP protein, human
  • Codon, Nonsense
  • Heterochromatin
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Nuclear Localization Signals
  • Proteasome Endopeptidase Complex

Grants and funding

This work was supported by the University of Antwerp, [BOF DOCPRO4] and grants from the ERA-NET NEURON through the Research Foundation – Flanders (FWO) and the Chief Scientist Office - Ministry of Health (CSO-MOH). GV is a postdoctoral fellow of the Research Fund Flanders (FWO).