American journal of human genetics, 2018-03-01, Vol.102 (3), p.468-479
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.
Abnormalities, Multiple - genetics ; Adolescent ; Amino Acid Sequence ; Analysis ; Animals ; Autism ; autism spectrum disorder ; BAF complex ; Child ; Child, Preschool ; Chlorocebus aethiops ; Coffin-Siris syndrome ; COS Cells ; DNA-Binding Proteins - chemistry ; DNA-Binding Proteins - genetics ; dominant negative ; DPF2 ; Face - abnormalities ; Facies ; Female ; Genetic aspects ; Genetics ; Hand Deformities, Congenital - genetics ; HEK293 Cells ; histone modification ; Histones - metabolism ; Human genetics ; Humans ; intellectual disability ; Intellectual Disability - genetics ; Life Sciences ; Male ; Medical research ; Medicine, Experimental ; Micrognathism - genetics ; Mutation - genetics ; nail hypoplasia ; Neck - abnormalities ; nuclear aggregates ; PHD finger ; Phenotype ; Protein Subunits - genetics ; Recombinant proteins ; Report ; Speech therapists ; Transcription Factors
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