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The causes are heterogeneous, with a monogenic basis identified in ~25% of patients. Using whole-genome sequencing, we identified a novel, de novo variant in BCL11B, c.7C&gt;A, encoding an R3S substitution (p.R3S), in a male patient with coronal suture synostosis. BCL11B is a transcription factor that interacts directly with the nucleosome remodelling and deacetylation complex (NuRD) and polycomb-related complex 2 (PRC2) through the invariant proteins RBBP4 and RBBP7. The p.R3S substitution occurs within a conserved amino-terminal motif (RRKQxxP) of BCL11B and reduces interaction with both transcriptional complexes. Equilibrium binding studies and molecular dynamics simulations show that the p.R3S substitution disrupts ionic coordination between BCL11B and the RBBP4\u2013MTA1 complex, a subassembly of the NuRD complex, and increases the conformational flexibility of Arg-4, Lys-5 and Gln-6 of BCL11B. These alterations collectively reduce the affinity of BCL11B p.R3S for the RBBP4\u2013MTA1 complex by nearly an order of magnitude. We generated a mouse model of the BCL11B p.R3S substitution using a CRISPR-Cas9-based approach, and we report herein that these mice exhibit craniosynostosis of the coronal suture, as well as other cranial sutures. This finding provides strong evidence that the BCL11B p.R3S substitution is causally associated with craniosynostosis and confirms an important role for BCL11B in the maintenance of cranial suture patency.<\/jats:p>","DOI":"10.1093\/hmg\/ddz072","type":"journal-article","created":{"date-parts":[[2019,4,2]],"date-time":"2019-04-02T07:21:56Z","timestamp":1554189716000},"page":"2501-2513","source":"Crossref","is-referenced-by-count":38,"title":["A de novo substitution in BCL11B leads to loss of interaction with transcriptional complexes and craniosynostosis"],"prefix":"10.1093","volume":"28","author":[{"given":"Jacqueline A C","family":"Goos","sequence":"first","affiliation":[{"name":"Departments of Plastic and Reconstructive Surgery and Hand Surgery"},{"name":"Bioinformatics, Erasmus MC, University Medical Center Rotterdam, CA Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter K","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hana","family":"Mlcochova","sequence":"additional","affiliation":[{"name":"Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J","family":"Millard","sequence":"additional","affiliation":[{"name":"Leicester Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elahe","family":"Esfandiari","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wisam H","family":"Selman","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, USA"},{"name":"College of Veterinary Medicine, University of Al-Qadisiyah, Al Diwaniyah, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Calpena","sequence":"additional","affiliation":[{"name":"Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils","family":"Koelling","sequence":"additional","affiliation":[{"name":"Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan L","family":"Carpenter","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrid M A","family":"Swagemakers","sequence":"additional","affiliation":[{"name":"Bioinformatics, Erasmus MC, University Medical Center Rotterdam, CA Rotterdam, The Netherlands"},{"name":"Department of Pathology, Erasmus MC, University Medical Center Rotterdam, CA Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J","family":"van der Spek","sequence":"additional","affiliation":[{"name":"Bioinformatics, Erasmus MC, University Medical Center Rotterdam, CA Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa M","family":"Filtz","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W R","family":"Schwabe","sequence":"additional","affiliation":[{"name":"Leicester Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urszula T","family":"Iwaniec","sequence":"additional","affiliation":[{"name":"Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene M J","family":"Mathijssen","sequence":"additional","affiliation":[{"name":"Departments of Plastic and Reconstructive Surgery and Hand Surgery"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Leid","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 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