Alternative titles; symbols
HGNC Approved Gene Symbol: DPF2
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38) : 11:65,333,852-65,354,262 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.1 | Coffin-Siris syndrome 7 | 618027 | Autosomal dominant | 3 |
The DPF2 gene encodes a noncatalytic subunit of the BAF chromatin-remodeling complex and plays a role in the epigenetic regulation of transcription through the identification of histone modifications (see, e.g., SMARCA4, BRG1, 603254) (summary by Vasileiou et al., 2018).
Chestkov et al. (1996) described a conserved human gene homologous to Neuro-d4 (DPF1; 601670) that they designated Ubi-d4. The human protein is the apparent homolog of the mouse Ubi-d4 protein, also known as Requiem (Gabig et al., 1994).
Apoptosis in murine myeloid cell lines requires expression of the Requiem gene, which encodes a putative zinc finger protein. A large consortium (Gabig et al., 1998) consisting of 3 groups detected the protein in both cytoplasmic and nuclear subcellular fractions of murine myeloid cells and human K562 leukemia cells, suggesting that the protein may have a function distinct from that of a transcription factor. The distribution did not alter upon apoptosis induction by IL3 deprivation. The gene was expressed in various tissues in early gestational ages; however, expression was confined to testis, spleen, thymus, and part of the hippocampus in the adult mouse. The expression profile was considered consistent with a functional role during rapid growth and cell turnover, and again suggested a regulatory function for hematopoietic cells. The nucleotide sequence of the human cDNA is 73% identical overall to that of the murine cDNA. The human sequence encodes a 391-amino acid protein.
Expression of Ubi-d4/requiem appeared to be required for apoptosis (Chestkov et al., 1996; Gabig et al., 1994).
Chestkov et al. (1996) mapped the DPF2 gene to chromosome 11q13 by fluorescence in situ hybridization.
By cohybridization fluorescence in situ hybridization on extended DNA fibers, Gabig et al. (1998) mapped the REQ gene between MLK3 (600050) and FAU (134690), which had been mapped to 11q13, telomeric to PYGM (608455). The physical distance between MLK3 and REQ was estimated to be 150 kb.
In 8 unrelated patients with Coffin-Siris syndrome-7 (CSS7; 618027), Vasileiou et al. (2018) identified 8 different de novo heterozygous mutations in the DPF2 gene (see, e.g., 601671.0001-601671.0005). There were 5 missense mutations, 2 splice site mutations, and 1 frameshift mutation. The missense mutations affected highly conserved residues in the PHD1 or PHD2 finger domains, which are responsible for the recognition of histone modifications. The mutations were close to zinc binding sites, most likely disrupting these sites and the protein structure. In vitro functional expression studies of 3 of the missense mutations (C276F, 601671.0001; C330W, 601671.0002; and R350H, 601671.0003) showed that they resulted in abolished or strongly attenuated binding to certain modified and unmodified H3 histone tails. In addition, expression of the mutations in HEK293 and COS-7 cells resulted in the formation of abnormal aggregate-like structures in the nucleus when expressed alone, and recruited wildtype DPF2 and BRG1 to the aggregates with coexpressed with those wildtype proteins. Theses findings were consistent with a dominant-negative pathomechanism. Analysis of the 2 splice site mutations and the frameshift mutation suggested that they escape nonsense-mediated mRNA decay, thus precluding haploinsufficiency and also supporting a dominant-negative mechanism. The patients were ascertained from large cohorts of patients with developmental disabilities and through web-based matching programs and collaboration. Six of the patients had additional rare single-nucleotide variants or copy number variants affecting other genes, which were not considered to affect the phenotype. Vasileiou et al. (2018) suggested that the mutations in nucleosome-targeting modules of the DPF2 gene disrupt PHD finger functional cohesion and capacity to recognize H3 histone modifications, leading to misreading from the BAF complex and epigenetic deregulation of gene transcription. The findings confirmed a crucial role of PHD-finger-containing proteins in human neurodevelopmental disorders.
In a 10-year-old boy (individual 1) with Coffin-Siris syndrome-7 (CSS7; 618027), Vasileiou et al. (2018) identified a de novo heterozygous c.827G-T transversion (c.827G-T, NM_006268.4) in exon 8 of the DPF2 gene, resulting in a cys276-to-phe (C276F) substitution at a highly conserved residue in the PHD1 finger domain. The mutation, which was found by exome sequencing, was not found in the gnomAD database.
In a 16-year-old girl (individual 2) with Coffin-Siris syndrome-7 (CSS7; 618027), Vasileiou et al. (2018) identified a de novo heterozygous c.990C-G transversion (c.990C-G, NM_006268.4) in exon 9 of the DPF2 gene, resulting in a cys330-to-trp (C330W) substitution at a highly conserved residue in the PHD2 finger domain. The mutation, which was found by exome sequencing, was not found in the gnomAD database.
In an 18.5-year-old girl (individual 3) with Coffin-Siris syndrome-7 (CSS7; 618027), Vasileiou et al. (2018) identified a de novo heterozygous c.1049G-A transition (c.1049G-A, NM_006268.4) in exon 10 of the DPF2 gene, resulting in an arg350-to-his (R350H) substitution at a highly conserved residue in the PHD2 finger domain. The mutation, which was found by exome sequencing, was not found in the gnomAD database.
In a boy (individual 4, DDDP126054) with Coffin-Siris syndrome-7 (CSS7; 618027), Vasileiou et al. (2018) identified a de novo heterozygous c.1037A-G transition (c.1037A-G, NM_006268.4) in exon 10 of the DPF2 gene, resulting in an asp346-to-gly (D346G) substitution at a highly conserved residue in the PHD2 finger domain. The mutation, which was found by exome sequencing, was not found in the gnomAD database.
In a 7-year-old girl (individual 7) with Coffin-Siris syndrome-7 (CSS7; 618027), Vasileiou et al. (2018) identified a de novo heterozygous G-to-A transition (c.1099+1G-A, NM_006268.4) in intron 10 of the DPF2 gene, resulting in the skipping of exon 10, a frameshift, and premature termination (Asp340GlufsTer12). The mutation, which was found by exome sequencing, was not found in the gnomAD database. Analysis of patient cells showed that the mutation escaped nonsense-mediated mRNA decay.
Chestkov, A. V., Baka, I. D., Kost, M. V., Georgiev, G. P., Buchman, V. L. The d4 gene family in the human genome. Genomics 36: 174-177, 1996. [PubMed: 8812431] [Full Text: https://doi.org/10.1006/geno.1996.0440]
Gabig, T. G., Crean, C. D., Klenk, A., Long, H., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Quincey, D., Parente, F., Lespinasse, F., Carle, G. F., Gaudray, P., and 13 others. Expression and chromosomal localization of the Requiem gene. Mammalian Genome 9: 660-665, 1998. [PubMed: 9680388] [Full Text: https://doi.org/10.1007/s003359900840]
Gabig, T. G., Mantel, P. L., Rosli, R., Crean, C. D. Requiem: a novel zinc finger gene essential for apoptosis in myeloid cells. J. Biol. Chem. 269: 29515-29519, 1994. [PubMed: 7961935]
Vasileiou, G., Vergarajauregui, S., Endele, S., Popp, B., Buttner, C., Ekici, A. B., Gerard, M., Bramswig, N. C., Albrecht, B., Clayton-Smith, J., Morton, J., Tomkins, S., and 18 others. Mutations in the BAF-complex subunit DPF2 are associated with Coffin-Siris syndrome. Am. J. Hum. Genet. 102: 468-479, 2018. [PubMed: 29429572] [Full Text: https://doi.org/10.1016/j.ajhg.2018.01.014]