Protein destabilization underlies pathogenic missense mutations in ARID1B

Nat Struct Mol Biol. 2024 Jul;31(7):1018-1022. doi: 10.1038/s41594-024-01229-2. Epub 2024 Feb 12.

Abstract

ARID1B is a SWI/SNF subunit frequently mutated in human Coffin-Siris syndrome (CSS) and it is necessary for proliferation of ARID1A mutant cancers. While most CSS ARID1B aberrations introduce frameshifts or stop codons, the functional consequence of missense mutations found in ARID1B is unclear. We here perform saturated mutagenesis screens on ARID1B and demonstrate that protein destabilization is the main mechanism associated with pathogenic missense mutations in patients with Coffin-Siris Syndrome.

MeSH terms

  • Abnormalities, Multiple / genetics
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Face / abnormalities
  • Hand Deformities, Congenital* / genetics
  • Humans
  • Intellectual Disability* / genetics
  • Micrognathism* / genetics
  • Mutation, Missense*
  • Neck / abnormalities
  • Protein Stability*
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism

Substances

  • DNA-Binding Proteins
  • Transcription Factors
  • ARID1B protein, human

Supplementary concepts

  • Coffin-Siris syndrome