Protein destabilization underlies pathogenic missense mutations in ARID1B

Fanny Mermet-Meillon; Samuele Mercan; Beatrice Bauer-Probst; Cyril Allard; Melusine Bleu; Keith Calkins; Judith Knehr; Marc Altorfer; Ulrike Naumann; Kathleen Sprouffske; Louise Barys; Fabian Sesterhenn; Giorgio G Galli

doi:10.1038/s41594-024-01229-2

Protein destabilization underlies pathogenic missense mutations in ARID1B

Nat Struct Mol Biol. 2024 Feb 12. doi: 10.1038/s41594-024-01229-2. Online ahead of print.

Affiliations

¹ Disease Area Oncology, Novartis Biomedical Research, Basel, Switzerland.
² Disease Area Immunology, Novartis Biomedical Research, Basel, Switzerland.
³ Discovery Sciences, Novartis Biomedical Research, Basel, Switzerland.
⁴ Discovery Sciences, Novartis Biomedical Research, Basel, Switzerland. fabian.sesterhenn@novartis.com.
⁵ Disease Area Oncology, Novartis Biomedical Research, Basel, Switzerland. giorgio.galli@novartis.com.

^# Contributed equally.

PMID: 38347147
DOI: 10.1038/s41594-024-01229-2

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.