Biology:PHF8

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

PHD finger protein 8 is a protein that in humans is encoded by the PHF8 gene.[1]

Function

PHF8 belongs to the family of ferrous iron and alpha-ketoglutarate-dependent hydroxylases superfamily.,[2] and is active as a histone lysine demethylase with selectivity for the di-and monomethyl states.[3] 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.[4]

Clinical significance

Mutations in PHF8 cause Siderius type X-linked intellectual disability (XLMR) (Online Mendelian Inheritance in Man (OMIM) 300263).[5][6][7] 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.[8][9][10] 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.[11]

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,[10] was found to additionally prevent nuclear localisation of PHF8 overexpressed in human cells.[3]

The catalytic activity of PHF8 depends on molecular oxygen,[3] 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.[12] In humans, fetal cleft lip and other congenital abnormalities have also been linked to maternal hypoxia, as caused by e.g. maternal smoking,[13] heavy maternal alcohol use, or maternal hypertension treatment.[14]

References

  1. ↑ "Entrez Gene: PHF8 PHD finger protein 8". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23133. 
  2. ↑ "Expanding chemical biology of 2-oxoglutarate oxygenases". Nature Chemical Biology 4 (3): 152–6. Mar 2008. doi:10.1038/nchembio0308-152. PMID 18277970. 
  3. ↑ 3.0 3.1 3.2 "PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an Nepsilon-dimethyl lysine demethylase". Human Molecular Genetics 19 (2): 217–22. Jan 2010. doi:10.1093/hmg/ddp480. PMID 19843542. 
  4. ↑ Boeckel, Jes-Niels; Derlet, Anja; Glaser, Simone F.; Luczak, Annika; Lucas, Tina; Heumüller, Andreas W.; Krüger, Marcus; Zehendner, Christoph M. et al. (July 2016). "JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial Cells". Arteriosclerosis, Thrombosis, and Vascular Biology 36 (7): 1425–1433. doi:10.1161/ATVBAHA.116.307695. ISSN 1524-4636. PMID 27199445. 
  5. ↑ "X-linked mental retardation associated with cleft lip/palate maps to Xp11.3-q21.3". American Journal of Medical Genetics 85 (3): 216–20. Jul 1999. doi:10.1002/(SICI)1096-8628(19990730)85:3<216::AID-AJMG6>3.0.CO;2-X. PMID 10398231. 
  6. ↑ "OMIM: Siderius X-linked mental retardation syndrome". https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300263. 
  7. ↑ "OMIM: PHD finger protein 8; PHF8". https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300560. 
  8. ↑ "A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate". Clinical Genetics 72 (1): 19–22. Jul 2007. doi:10.1111/j.1399-0004.2007.00817.x. PMID 17594395. 
  9. ↑ "Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate". Journal of Medical Genetics 42 (10): 780–6. Oct 2005. doi:10.1136/jmg.2004.029439. PMID 16199551. 
  10. ↑ 10.0 10.1 "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 72 (2): 145–9. Aug 2007. doi:10.1111/j.1399-0004.2007.00836.x. PMID 17661819. 
  11. ↑ "Autism-associated familial microdeletion of Xp11.22". Clinical Genetics 74 (2): 134–44. Aug 2008. doi:10.1111/j.1399-0004.2008.01028.x. PMID 18498374. 
  12. ↑ "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 78 (9): 5722–3. Sep 1981. doi:10.1073/pnas.78.9.5722. PMID 6946511. Bibcode: 1981PNAS...78.5722M. 
  13. ↑ "Review on genetic variants and maternal smoking in the etiology of oral clefts and other birth defects". Birth Defects Research. Part C, Embryo Today 84 (1): 16–29. Mar 2008. doi:10.1002/bdrc.20117. PMID 18383123. 
  14. ↑ "Transverse limb deficiency, facial clefting and hypoxic renal damage: an association with treatment of maternal hypertension?". Clinical Dysmorphology 4 (4): 359–63. Oct 1995. doi:10.1097/00019605-199510000-00013. PMID 8574428. 

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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