Mutations in the BAF-complex subunit DPF2 are associated with Coffin-Siris syndrome

Item Type:	Article
Title:	Mutations in the BAF-complex subunit DPF2 are associated with Coffin-Siris syndrome
Creators Name:	Vasileiou, G. and Vergarajauregui, S. and Endele, S. and Popp, B. and Büttner, C. and Ekici, A.B. and Gerard, M. and Bramswig, N.C. and Albrecht, B. and Clayton-Smith, J. and Morton, J. and Tomkins, S. and Low, K. and Weber, A. and Wenzel, M. and Altmüller, J. and Li, Y. and Wollnik, B. and Hoganson, G. and Plona, M.R. and Cho, M.T. and Thiel, C.T. and Lüdecke, H.J. and Strom, T.M. and Calpena, E. and Wilkie, A.O.M. and Wieczorek, D. and Engel, F.B. and Reis, A.
Abstract:	Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). Affected individuals share common clinical features described in individuals with Coffin-Siris syndrome, including coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. All variants occur within the highly conserved PHD1 and PHD2 motifs. Moreover, missense variants are situated close to zinc binding sites and are predicted to disrupt these sites. Pull-down assays of recombinant proteins and histone peptides revealed that a subset of the identified missense variants abolish or impaire DPF2 binding to unmodified and modified H3 histone tails. These results suggest an impairment of PHD finger structural integrity and cohesion and most likely an aberrant recognition of histone modifications. Furthermore, the overexpression of these variants in HEK293 and COS7 cell lines was associated with the formation of nuclear aggregates and the recruitment of both wild-type DPF2 and BRG1 to these aggregates. Expression analysis of truncating variants found in the affected individuals indicated that the aberrant transcripts escape nonsense-mediated decay. Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity.
Keywords:	Coffin-Siris Syndrome, BAF Complex, DPF2, PHD Finger, Intellectual Disability, Autism Spectrum Disorder, Histone Modification, Nuclear Aggregates, Dominant Negative, Nail Hypoplasia, Animals
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	102
Number:	3
Page Range:	468-479
Date:	1 March 2018
Official Publication:	https://doi.org/10.1016/j.ajhg.2018.01.014
PubMed:	View item in PubMed

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