Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals

Bosch, Elisabeth; Popp, Bernt; Güse, Esther; Skinner, Cindy; Sluijs, Pleuntje J. van der; Maystadt, Isabelle; Pinto, Anna Maria; Renieri, Alessandra; Bruno, Lucia Pia; Granata, Stefania; Marcelis, Carlo; Baysal, Özlem; Hartwich, Dewi; Holthöfer, Laura; Isidor, Bertrand; Cogné, Benjamin; Wieczorek, Dagmar; Capra, Valeria; Scala, Marcello; Marco, Patrizia De; Ognibene, Marzia; Jamra, Rami Abou; Platzer, Konrad; Carter, Lauren B.; Kuismin, Outi; Haeringen, Arie van; Maroofian, Reza; Valenzuela, Irene; Cuscò, Ivon; Martinez‐Agosto, Julian A.; Rabani, Ahna M.; Mefford, Heather C; Pereira, Elaine M.; Close, Charlotte; Anyane‐Yeboa, Kwame; Wagner, Mallory; Hannibal, Mark C.; Zacher, Pia; Thiffault, Isabelle; Beunders, Gea; Umair, Muhammad; Bhola, Priya T.; McGinnis, Erin; Millichap, J; Kamp, Jiddeke M. van de; Prijoles, Eloise J.; Dobson, Amy; Shillington, Amelle; Graham, Brett H.; Garcia, E. Grau; Galindo, Maureen Kelly; Ropers, Fabienne G.; Nibbeling, Esther; Hubbard, Gail; Karimov, Catherine; Goj, Guido; Bend, Renee; Rath, Julie; Morrow, Michelle M.; Millan, Francisca; Salpietro, Vincenzo; Torella, Annalaura; Nigro, Vincenzo; Kurki, Mitja; Stevenson, Roger E.; Santen, Gijs W.E.; Zweier, Christiane; Campeau, Philippe M.; Severino, Mariasavina; Reis, André; Accogli, Andrea; Vasileiou, Georgia

doi:10.1016/j.gim.2023.100950

Cited by 5 publications

(3 citation statements)

References 37 publications

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“…With regards to NDDs -'BAFopathies' -genes coding for cBAF subunits possess most de novo missense and proteintruncating mutations among all nuclear protein complexes 28 . Also, biallelic mutations in the neuronspecific ACTL6B or haplosufficiency of ARID1B causes recessively inherited autism 24,85 , microduplication of ARID1A causes intellectual disability 92 , and SMARCC2 is a high-confidence autism gene [93][94][95][96][97] . As for brain tumors, SMARCA4 is recurrently mutated in multiple cancers 98 .…”

Section: Discussionmentioning

confidence: 99%

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

Cornejo,

Venegas,

Sono

et al. 2023

Preprint

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Signal-dependent RNA Polymerase II (Pol2) productive elongation is an integral component of gene transcription, including those of immediate early genes (IEGs) induced by neuronal activity. However, it remains unclear how productively elongating Pol2 overcome nucleosomal barriers. Using RNAi, three degraders, and several small molecule inhibitors, we show that the mammalian SWI/SNF complex of neurons (neuronal BAF, or nBAF) is required for activity-induced transcription of neuronal IEGs, including Arc. The nBAF complex facilitates promoter-proximal Pol2 pausing, signal-dependent Pol2 recruitment (loading), and importantly, mediates productive elongation in the gene body via interaction with the elongation complex and elongation-competent Pol2. Mechanistically, Pol2 elongation is mediated by activity-induced nBAF assembly (especially, ARID1A recruitment) and its ATPase activity. Together, our data demonstrate that the nBAF complex regulates several aspects of Pol2 transcription and reveal mechanisms underlying activity-induced Pol2 elongation. These findings may offer insights into human maladies etiologically associated with mutational interdiction of BAF functions.

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Section: Discussionmentioning

confidence: 99%

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

Cornejo,

Venegas,

Sono

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Plasmids were transfected into HEK293T or HeLa cells using JetPrime (Polyplus Life Science). Immuno uorescence staining and protein stability assessments were performed as previously described (Bosch et al 2023b). Co-immunoprecipitation was performed using Dynabeads (Thermo Fisher Scienti c).…”

Section: Array-based Dna Methylation Analysismentioning

confidence: 99%

“…The most well de ned BAFopathy, caused by pathogenic variants in several BAF subunit genes including ARID1A, ARID1B, SMARCA4, SMARCC2, SMARCB1, SMARCE1, DPF2, and BICRA, is the autosomal dominant Co n-Siris syndrome (CSS; MIM 135900) (Hoyer et Bosch et al 2023a). The clinical spectrum is highly variable, ranging from mild to severe, partly depending on the affected BAF subunit.…”

Section: Introductionmentioning

confidence: 99%

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

Bosch,

Güse,

Kirchner

et al. 2024

Preprint

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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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Delineation of the adult phenotype of Coffin–Siris syndrome in 35 individuals

Schmetz,

Lüdecke,

Surowy

et al. 2023

Hum. Genet.

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Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals

Cited by 5 publications

References 37 publications

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

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

Delineation of the adult phenotype of Coffin–Siris syndrome in 35 individuals

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