PHF8

Function

PHF8 belongs to the family of ferrous iron and alpha-ketoglutarate-dependent hydroxylases superfamily., and is active as a histone lysine demethylase with selectivity for the di-and monomethyl states. PHF8 induces an EMT (epithelial to mesenchymal transition)-like process by upregulating key EMT transcription factors SNAI1 and ZEB1.

Regulation during differentiation

PHF8 was found to be expressional increased during endothelial differentiation and significantly decreased during cardial differentiation of murine embryonic stem cells.

Clinical significance

Mutations in PHF8 cause Siderius type X-linked intellectual disability (XLMR) (). In addition to moderate intellectual disability, features of the Siderius-Hamel syndrome include facial dysmorphism, cleft lip and/or cleft palate, and in some cases microcephaly. A chromosomal microdeletion on Xp11.22 encompassing all of the PHF8 and FAM120C genes and a part of the WNK3 gene was reported in two brothers with autism spectrum disorder in addition to Siderius-type XLMR and cleft lip and palate.

This catalytic activity is disrupted by clinically known mutations to PHF8, which were found to cluster in its catalytic JmjC domain. The F279S mutation of PHF8, found in 2 Finnish brothers with mild intellectual disability, facial dysmorphism and cleft lip/palate, was found to additionally prevent nuclear localisation of PHF8 overexpressed in human cells.

The catalytic activity of PHF8 depends on molecular oxygen, a fact considered important with respect to reports on increased incidence of cleft lip/palate in mice that have been exposed to hypoxia during pregnancy. In humans, fetal cleft lip and other congenital abnormalities have also been linked to maternal hypoxia, as caused by e.g. maternal smoking, heavy maternal alcohol use, or maternal hypertension treatment.

References

References

1. "Entrez Gene: PHF8 PHD finger protein 8".
2. (Mar 2008). "Expanding chemical biology of 2-oxoglutarate oxygenases". Nature Chemical Biology.
3. (Jan 2010). "PHF8, a gene associated with cleft lip/palate and intellectual disability, encodes for an Nepsilon-dimethyl lysine demethylase". Human Molecular Genetics.
4. (July 2016). "JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial Cells". Arteriosclerosis, Thrombosis, and Vascular Biology.
5. (Jul 1999). "X-linked mental retardation associated with cleft lip/palate maps to Xp11.3-q21.3". American Journal of Medical Genetics.
6. (July 2025). "OMIM: Siderius X-linked mental retardation syndrome".
7. (July 2025). "OMIM: PHD finger protein 8; PHF8".
8. (Jul 2007). "A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate". Clinical Genetics.
9. (Oct 2005). "Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate". Journal of Medical Genetics.
10. (Aug 2007). "Screening of mutations in the PHF8 gene and identification of a novel mutation in a Finnish family with XLMR and cleft lip/cleft palate". Clinical Genetics.
11. (Aug 2008). "Autism-associated familial microdeletion of Xp11.22". Clinical Genetics.
12. (July 2022). "Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology". HGG Advances.
13. (Sep 1981). "Hyperoxia and hypoxia in pregnancy: simple experimental manipulation alters the incidence of cleft lip and palate in CL/Fr mice". Proceedings of the National Academy of Sciences of the United States of America.
14. (Mar 2008). "Review on genetic variants and maternal smoking in the etiology of oral clefts and other birth defects". Birth Defects Research. Part C, Embryo Today.
15. (Oct 1995). "Transverse limb deficiency, facial clefting and hypoxic renal damage: an association with treatment of maternal hypertension?". Clinical Dysmorphology.