TY - JOUR
T1 - Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris Syndrome
AU - Vasileiou, Georgia
AU - Vergarajauregui, Silvia
AU - Endele, Sabine
AU - Popp, Bernt
AU - Büttner, Christian
AU - Ekici, Arif B.
AU - Gerard, Marion
AU - Bramswig, Nuria C.
AU - Albrecht, Beate
AU - Clayton-Smith, Jill
AU - Morton, Jenny
AU - Tomkins, Susan
AU - Low, Karen
AU - Weber, Astrid
AU - Wenzel, Maren
AU - Altmüller, Janine
AU - Li, Yun
AU - Wollnik, Bernd
AU - Hoganson, George
AU - Plona, Maria Renée
AU - Cho, Megan T.
AU - Thiel, Christian T.
AU - Lüdecke, Hermann Josef
AU - Strom, Tim M.
AU - Calpena, Eduardo
AU - Wilkie, Andrew O.M.
AU - Wieczorek, Dagmar
AU - Engel, Felix B.
AU - Reis, André
AU - Deciphering Developmental Disorders Study
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
KW - autism spectrum disorder
KW - BAF complex
KW - Coffin-Siris syndrome
KW - dominant negative
KW - DPF2
KW - histone modification
KW - intellectual disability
KW - nail hypoplasia
KW - nuclear aggregates
KW - PHD finger
UR - http://www.scopus.com/inward/record.url?scp=85041640977&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2018.01.014
DO - 10.1016/j.ajhg.2018.01.014
M3 - Article
AN - SCOPUS:85041640977
SN - 0002-9297
VL - 102
SP - 468
EP - 479
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -