Alternative titles; symbols
HGNC Approved Gene Symbol: PHF8
SNOMEDCT: 718908009;
Cytogenetic location: Xp11.22 Genomic coordinates (GRCh38) : X:53,936,680-54,048,936 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.22 | Intellectual developmental disorder, X-linked syndromic, Siderius type | 300263 | X-linked recessive | 3 |
PHF8 belongs to the plant homeodomain (PHD) finger (PHF) protein family of PHD- and Jumonji domain-containing histone demethylases. PHF8 catalyzes removal of dimethylated histone-3 (H3; see 602810) lys9 (H3K9m2) on promoters of its target genes (Horton et al., 2010).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Kikuno et al. (1999) cloned PHF8, which they designated KIAA1111. The deduced 1,084-amino acid protein contains a PHD finger motif. RT-PCR ELISA detected highest PHF8 expression in ovary. Expression was intermediate in all other adult and fetal tissues and specific brain regions examined.
Horton et al. (2010) noted that the N-terminal region of human PHF8 harbors a PHD that binds H3K4me3 and a Jumonji domain that demethylates H3K9me2. The domains are connected by a linker.
By radiation hybrid analysis, Kikuno et al. (1999) mapped the PHF8 gene to chromosome X.
Loenarz et al. (2010) reported that recombinant PHF8 is an Fe(II) and 2-oxoglutarate-dependent N-epsilon-methyl lysine demethylase, which acts on histone substrates. PHF8 is selective in vitro for N-epsilon-di- and monomethylated lysine residues and does not accept trimethyl substrates. Clinically observed mutations to the PHF8 gene cluster in exons encoding for the double-stranded beta-helix fold and are expected to disrupt catalytic activity. The PHF8 F279S mutation (300560.0004), which is associated with mild MR, mild dysmorphic features, and cleft lip and palate, modifies a conserved hydrophobic region, rendering the enzyme catalytically inactive. Loenarz et al. (2010) hypothesized that dependence of PHF8 activity on oxygen availability may explain an association between maternal hypoxia and facial clefting.
Qi et al. (2010) provided multiple lines of evidence establishing PHF8 as the first monomethyl histone H4 lysine-20 (H4K20me1) demethylase, with additional activities towards histone H3K9me1 and me2. PHF8 is located around the transcriptional start sites of approximately 7,000 RefSeq genes and in gene bodies and intergenic regions. PHF8 depletion resulted in upregulation of H4K20me1 and H3K9me1 at the transcriptional start site and H3K9me2 in the nontranscriptional start sites, respectively, demonstrating differential substrate specificities at different target locations. PHF8 positively regulates gene expression, which is dependent on its H3K4me3-binding PHD and catalytic domains. Importantly, patient mutations significantly compromised PHF8 catalytic function. PHF8 regulates cell survival in the zebrafish brain and jaw development, thus providing a potentially relevant biologic context for understanding the clinical symptoms associated with PHF8 patients. Lastly, genetic and molecular evidence supported a model whereby PHF8 regulates zebrafish neuronal cell survival and jaw development in part by directly regulating the expression of the homeodomain transcription factor MSX1/MSXB (605558), which functions downstream of multiple signaling and developmental pathways. Qi et al. (2010) concluded that their findings indicated that an imbalance of histone methylation dynamics has a critical role in X-linked mental retardation.
Liu et al. (2010) reported that PHF8, while using multiple substrates, including H3K9me1/2 and H3K27me2, also functions as an H4K20me1 demethylase.
Using a fluorescence-based demethylation assay, Horton et al. (2010) showed that the presence of H3K4me3 on the same peptide as H3K9me2 enhanced PHF8 demethylation activity on H3K9me2. In contrast, the presence of H3K4me3 on the same peptide with H3K9me2 inhibited KIAA1718 (KDM7A; 619640) demethylation activity on H3K9me2.
PHF8 is recruited to promoters by its PHD domain based on interaction with H3K4me2/3 and controls G1-S transition in conjunction with E2F1, HCF1 (300019), and SET1A (611052), at least in part, by removing the repressive H4K20me1 mark from a subset of E2F1-regulated gene promoters. Phosphorylation-dependent PHF8 dismissal from chromatin in prophase is apparently required for the accumulation of H4K20me1 during early mitosis, which might represent a component of the condensin II loading process. Accordingly, the HEAT repeat clusters in 2 non-structural maintenance of chromosomes (SMC) condensin II subunits, NCAPD3 (609276) and NCAPG2 (608532), are capable of recognizing H4K20me1, and ChIP-Seq analysis demonstrated a significant overlap of condensin II and H4K20me1 sites in mitotic HeLa cells. Thus, Liu et al. (2010) concluded that the identification and characterization of an H4K20me1 demethylase, PHF8, has revealed an intimate link between this enzyme and 2 distinct events in cell cycle progression.
Horton et al. (2010) determined the cocrystal structures of PHF8 or KIAA1718 in complex with a dimethylated peptide containing H3K4me3 and H3K9me2 at 2.2- or 2.4-angstrom resolution, respectively. The structures revealed that the PHD and Jumonji domains of these proteins acted in concert in substrate recognition. Interactions of H3K4me3 with the PHD of PHF8 promoted demethylation activity on H3K9me2 by its Jumonji domain, as PHF8 adopted a bent conformation that allowed its PHD and Jumonji domains to engage their respective targets efficiently. In contrast, KIAA1718 adopted an extended conformation due to its longer linker region compared with PHF8, which prevented the access to H3K9me2 by the Jumonji domain for demethylation. However, adoption of an extended conformation by KIAA1718 allowed it to selectively demethylate H3K27me2 when H3K4me3 was present in cis in a trimethylated H3K4 peptide or in trans on different peptides, as H3K27me2 could occupy both PHD and Jumonji domains simultaneously and could be demethylated by KIAA1718 in its extended conformation.
In the affected males with X-linked syndromic intellectual developmental disorder (MRXSSD; 300263) reported by Siderius et al. (1999), Laumonnier et al. (2005) identified a deletion in the PHF8 gene (300560.0001). Subsequent screening of another family with mental retardation and similar clinical features revealed a nonsense mutation in PHF8 (300560.0002).
Koivisto et al. (2007) identified a mutation in the PHF8 gene (300560.0004) in 2 Finnish brothers with MRXSSD. Both sibs had cleft lip/palate.
In a male with MRXSSD, Abidi et al. (2007) identified a nonsense mutation in the PHF8 gene (K177X; 300460.0003).
In 16 individuals with MRXSSD from 11 different families of diverse ancestry, Sobering et al. (2022) identified mutations in the PHF8 gene (see, e.g., 300560.0005). The mutations included 5 frameshift, 3 splice site, 2 nonsense, and 1 deletion. Eight were inherited from unaffected mothers and 3 occurred de novo. The authors also identified 4 previously unreported missense variants of unknown significance in 5 individuals with an intellectual developmental disorder; all were maternally inherited from unaffected mothers.
In 3 affected males from a family with Siderius X-linked syndromic intellectual developmental disorder (MRXSSD; 300263), previously described by Siderius et al. (1999), Laumonnier et al. (2005) identified a 12-bp deletion at the exon 8/intron 8 junction, predicted to suppress the splice donor site of intron 8.
In a 25-year-old male from a family with Siderius-type X-linked syndromic intellectual developmental disorder (MRXSSD; 300263), Laumonnier et al. (2005) identified a 631C-T transition in exon 7 of the PHF8 gene, resulting in an arg211-to-ter (R211X) substitution predicted to truncate the protein. Three deceased maternal uncles had mental retardation and/or cleft lip and palate; the patient's mother and maternal grandmother were heterozygous for the mutation.
In a male with impaired intellectual development, microcephaly, and cleft lip and palate (MRXSSD; 300263), Abidi et al. (2007) identified a 529A-T transversion in exon 6 of the PHF8 gene, resulting in a lys177-to-ter mutation. The predicted protein lacks the Jumonji-like C terminus domain and 5 nuclear localization signals. The proband's mother did not have the mutation, indicating that the mutation occurred de novo.
In 2 Finnish brothers with Siderius-type X-linked syndromic intellectual developmental disorder (MRXSSD; 300263), Koivisto et al. (2007) identified a hemizygous 836C-T transition in the PHF8 gene, resulting in a phe279-to-ser (F279S) substitution in the Jumonji-like C terminus domain of the protein. The clinical phenotype included mild mental retardation, facial dysmorphism, and cleft lip/palate. The unaffected mother was a carrier of the mutation. Several deceased male family members were reportedly affected.
In a boy with Siderius-type X-linked syndromic intellectual developmental disorder (MRXSSD; 300263), Sobering et al. (2022) identified a 1-bp insertion (c.738_739insT, NM_015107.2) in the PHF8 gene, predicted to result in a frameshift and a premature termination codon (His247SerfsTer3). The mutation, which was found by trio exome sequencing, was inherited from the unaffected mother.
Abidi, F. E., Miano, M. G., Murray, J. C., Schwartz, C. E. A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate. Clin. Genet. 72: 19-22, 2007. [PubMed: 17594395] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00817.x]
Horton, J. R., Upadhyay, A. K., Qi, H. H., Zhang, X., Shi, Y., Cheng, X. Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases. Nature Struct. Molec. Biol. 17: 38-43, 2010. [PubMed: 20023638] [Full Text: https://doi.org/10.1038/nsmb.1753]
Kikuno, R., Nagase, T., Ishikawa, K., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 197-205, 1999. [PubMed: 10470851] [Full Text: https://doi.org/10.1093/dnares/6.3.197]
Koivisto, A. M., Ala-Mello, S., Lemmela, S., Komu, H.A., Rautio, J., Jarvela, I. Screening of mutations in the PHF8 gene and identification of a novel mutation in a Finnish family with XLMR and cleft lip/cleft palate. Clin. Genet. 72: 145-149, 2007. [PubMed: 17661819] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00836.x]
Laumonnier, F., Holbert, S., Ronce, N., Faravelli, F., Lenzner, S., Schwartz, C. E., Lespinasse, J., Van Esch, H., Lacombe, D., Goizet, C., Phan-Dinh Tuy, F., van Bokhoven, H., Fryns, J.-P., Chelly, J., Ropers, H.-H., Moraine, C., Hamel, B. C. J., Briault, S. Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. J. Med. Genet. 42: 780-786, 2005. [PubMed: 16199551] [Full Text: https://doi.org/10.1136/jmg.2004.029439]
Liu, W., Tanasa, B., Tyurina, O. V., Zhou, T. Y., Gassmann, R., Liu, W. T., Ohgi, K. A., Benner, C., Garcia-Bassets, I., Aggarwal, A. K., Desai, A., Dorrestein, P. C., Glass, C. K., Rosenfeld, M. G. PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression. Nature 466: 508-512, 2010. [PubMed: 20622854] [Full Text: https://doi.org/10.1038/nature09272]
Loenarz, C., Ge, W., Coleman, M. L., Rose, N. R., Cooper, C. D. O., Klose, R. J., Ratcliffe, P. J., Schofield, C. J. PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an N-epsilon-dimethyl lysine demethylase. Hum. Molec. Genet. 19: 217-222, 2010. [PubMed: 19843542] [Full Text: https://doi.org/10.1093/hmg/ddp480]
Qi, H. H., Sarkissian, M., Hu, G.-Q., Wang, Z., Bhattacharjee, A., Gordon, D. B., Gonzales, M., Lan, F., Ongusaha, P. P., Huarte, M., Yaghi, N. K., Lim, H., Garcia, B. A., Brizuela, L., Zhao, K., Roberts, T. M., Shi, Y. Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature 466: 503-507, 2010. [PubMed: 20622853] [Full Text: https://doi.org/10.1038/nature09261]
Siderius, L. E., Hamel, B. C. J., van Bokhoven, H., de Jager, F., van den Helm, B., Kremer, H., Heineman-de Boer, J. A., Ropers, H.-H., Mariman, E. C. M. X-linked mental retardation associated with cleft lip/palate maps to Xp11.3-q21.3. Am. J. Med. Genet. 85: 216-220, 1999. [PubMed: 10398231]
Sobering, A. K., Bryant, L. M., Li, D., McGaughran, J., Maystadt, I., Moortgat, S., Graham, J. M., van Haeringen, A., Ruivenkamp, C., Cuperus, R., Vogt, J., Morton, J., and 28 others. Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology. Hum. Genet. Genomics Adv. 3: 100102, 2022. Note: Erratum: Hum. Genet. Genomics Adv. 4: 100168, 2023. [PubMed: 35469323] [Full Text: https://doi.org/10.1016/j.xhgg.2022.100102]