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The missing link: ARID1B non-truncating variants causing Coffin-Siris syndrome due to protein aggregation.
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.
Afiliación
  • Bosch E; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
  • Güse E; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
  • Kirchner P; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
  • Winterpacht A; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
  • Walther M; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
  • Alders M; Amsterdam University Medical Center, University of Amsterdam, Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.
  • Kerkhof J; Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada.
  • Ekici AB; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
  • Sticht H; Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
  • Sadikovic B; Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada.
  • Reis A; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
  • Vasileiou G; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
Hum Genet ; 143(8): 965-978, 2024 Aug.
Article en En | MEDLINE | ID: mdl-39028335
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Deformidades Congénitas de la Mano / Proteínas de Unión al ADN / Cara / Discapacidad Intelectual / Micrognatismo / Cuello Límite: Humans / Male Idioma: En Revista: Hum Genet Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Deformidades Congénitas de la Mano / Proteínas de Unión al ADN / Cara / Discapacidad Intelectual / Micrognatismo / Cuello Límite: Humans / Male Idioma: En Revista: Hum Genet Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Alemania