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:
CreatorsEmailORCIDORCID Put Code
Vasileiou, GeorgiaUNSPECIFIEDorcid.org/0000-0002-1993-1134UNSPECIFIED
Vergarajauregui, SilviaUNSPECIFIEDorcid.org/0000-0002-9247-6123UNSPECIFIED
Endele, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Popp, BerntUNSPECIFIEDorcid.org/0000-0002-3679-1081UNSPECIFIED
Buettner, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ekici, Arif B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerard, MarionUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bramswig, Nuria C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Albrecht, BeateUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clayton-Smith, JillUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morton, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tomkins, SusanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Low, KarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, AstridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wenzel, MarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, YunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoganson, GeorgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plona, Maria-ReneeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cho, Megan T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiel, Christian T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luedecke, Hermann-JosefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strom, Tim M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Calpena, EduardoUNSPECIFIEDorcid.org/0000-0001-6399-6528UNSPECIFIED
Wilkie, Andrew O. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wieczorek, DagmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engel, Felix B.UNSPECIFIEDorcid.org/0000-0003-2605-3429UNSPECIFIED
Reis, AndreUNSPECIFIEDorcid.org/0000-0002-6301-6363UNSPECIFIED
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:
KeywordsLanguage
CHROMATIN-REMODELING COMPLEX; DE-NOVO MUTATIONS; PHD FINGER; SWI/SNF COMPLEX; GENOTYPE-PHENOTYPE; HISTONE-BINDING; GENE; COMPONENTS; ARID1B; INDIVIDUALSMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19310

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