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Cited by 9Genomics and Rare DiseasesGenetics and Neurodevelopmental DisordersChromatin Remodeling and Cancer

The missing link: ARID1B non-truncating variants causing Coffin-Siris syndrome due to protein aggregation

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Bosch, Elisabeth, Güse, Esther, Kirchner, Philipp, Winterpacht, Andreas, Walther, Mona, Alders, Marielle, Kerkhof, Jennifer, Ekici, Arif B., Sticht, Heinrich, Sadikovic, Bekim, Reis, André, Vasileiou, Georgia·2024·Human Genetics
DOI 10.1007/s00439-024-02688-9PMC PMC11303441

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Abstract

ARID1B is the most frequently mutated gene in Coffin-Siris syndrome (CSS). To date, the vast majority of causative variants reported in ARID1B are truncating, leading to nonsense-mediated mRNA decay. In the absence of experimental data, only few ARID1B amino acid substitutions have been classified as pathogenic, mainly based on clinical data and their de novo occurrence, while most others are currently interpreted as variants of unknown significance. The present study substantiates the pathogenesis of ARID1B non-truncating/NMD-escaping variants located in the SMARCA4-interacting EHD2 and DNA-binding ARID domains. Overexpression assays in cell lines revealed that the majority of EHD2 variants lead to protein misfolding and formation of cytoplasmic aggresomes surrounded by vimentin cage-like structures and co-localizing with the microtubule organisation center. ARID domain variants exhibited not only aggresomes, but also nuclear aggregates, demonstrating robust pathological effects. Protein levels were not compromised, as shown by quantitative western blot analysis. In silico structural analysis predicted the exposure of amylogenic segments in both domains due to the nearby variants, likely causing this aggregation. Genome-wide transcriptome and methylation analysis in affected individuals revealed expression and methylome patterns consistent with those of the pathogenic haploinsufficiency ARID1B alterations in CSS cases. These results further support pathogenicity and indicate two approaches for disambiguation of such variants in everyday practice. The few affected individuals harbouring EHD2 non-truncating variants described to date exhibit mild CSS clinical traits. In summary, this study paves the way for the re-evaluation of previously unclear ARID1B non-truncating variants and opens a new era in CSS genetic diagnosis.

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Authors
Bosch, E., Güse, E., Kirchner, P., Winterpacht, A., Walther, M., Alders, M., Kerkhof, J., Ekici, A. B., Sticht, H., Sadikovic, B., Reis, A., & Vasileiou, G.
Affiliations
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • Amsterdam University Medical Centers (NL)
  • London Health Sciences Centre (CA)
Corresponding author
Vasileiou, Georgia
ORCID
Venue
Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2024-07-19
Volume
143
Issue
8
Pages
965-978
ISSN
  • 0018-7348 (ISSN-L)
  • 0340-6717
  • 1432-1203
DOI
10.1007/s00439-024-02688-9
PMC
PMC11303441
OpenAlex
W4400813488
Cited by
9
References
3
Citations by year
2026: 6 · 2025: 3
FWCI
2.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Human Genetics (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PUBLISSO (German National Library of Medicine) (submittedVersion, cc-by)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
Funders
Universitätsklinikum Erlangen
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
ARID1B, Coffin-Siris syndrome, EHD2, ARID domain, protein aggregation, aggresomes, nonsense-mediated mRNA decay, haploinsufficiency, DNA methylation, transcriptome, genetic diagnosis, variant interpretation
MeSH terms
Abnormalities, Multiple, DNA-Binding Proteins, Face, Hand Deformities, Congenital, Humans, Male, Intellectual Disability, Micrognathism, Mutation, Neck, Transcription Factors, Protein Aggregates

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