Universität zu Köln

Vasileiou, Georgia ORCID: 0000-0002-1993-1134, Vergarajauregui, Silvia ORCID: 0000-0002-9247-6123, Endele, Sabine, Popp, Bernt ORCID: 0000-0002-3679-1081, Buettner, Christian, Ekici, Arif B., Gerard, Marion, Bramswig, Nuria C., Albrecht, Beate, Clayton-Smith, Jill, Morton, Jenny, Tomkins, Susan, Low, Karen, Weber, Astrid, Wenzel, Maren, Altmueller, Janine, Li, Yun, Wollnik, Bernd, Hoganson, George, Plona, Maria-Renee, Cho, Megan T., Thiel, Christian T., Luedecke, Hermann-Josef, Strom, Tim M., Calpena, Eduardo ORCID: 0000-0001-6399-6528, Wilkie, Andrew O. M., Wieczorek, Dagmar, Engel, Felix B. ORCID: 0000-0003-2605-3429 and Reis, Andre ORCID: 0000-0002-6301-6363 (2018). Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris Syndrome. Am. J. Hum. Genet., 102 (3). S. 468 - 480. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Vasileiou, Georgia UNSPECIFIED orcid.org/0000-0002-1993-1134 UNSPECIFIED Vergarajauregui, Silvia UNSPECIFIED orcid.org/0000-0002-9247-6123 UNSPECIFIED Endele, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Popp, Bernt UNSPECIFIED orcid.org/0000-0002-3679-1081 UNSPECIFIED Buettner, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Ekici, Arif B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerard, Marion UNSPECIFIED UNSPECIFIED UNSPECIFIED Bramswig, Nuria C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Albrecht, Beate UNSPECIFIED UNSPECIFIED UNSPECIFIED Clayton-Smith, Jill UNSPECIFIED UNSPECIFIED UNSPECIFIED Morton, Jenny UNSPECIFIED UNSPECIFIED UNSPECIFIED Tomkins, Susan UNSPECIFIED UNSPECIFIED UNSPECIFIED Low, Karen UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Astrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Wenzel, Maren UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Yun UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoganson, George UNSPECIFIED UNSPECIFIED UNSPECIFIED Plona, Maria-Renee UNSPECIFIED UNSPECIFIED UNSPECIFIED Cho, Megan T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiel, Christian T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Luedecke, Hermann-Josef UNSPECIFIED UNSPECIFIED UNSPECIFIED Strom, Tim M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Calpena, Eduardo UNSPECIFIED orcid.org/0000-0001-6399-6528 UNSPECIFIED Wilkie, Andrew O. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wieczorek, Dagmar UNSPECIFIED UNSPECIFIED UNSPECIFIED Engel, Felix B. UNSPECIFIED orcid.org/0000-0003-2605-3429 UNSPECIFIED Reis, Andre UNSPECIFIED orcid.org/0000-0002-6301-6363 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-193100
DOI:	10.1016/j.ajhg.2018.01.014
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	102
Number:	3
Page Range:	S. 468 - 480
Date:	2018
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHROMATIN-REMODELING COMPLEX; DE-NOVO MUTATIONS; PHD FINGER; SWI/SNF COMPLEX; GENOTYPE-PHENOTYPE; HISTONE-BINDING; GENE; COMPONENTS; ARID1B; INDIVIDUALS Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19310