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 2-oxoglutarate dependent oxygenases,[2] and is active as a histone lysine demethylase with selectivity for the di-and monomethyl states.[3]
Clinical significance
Mutations in PHF8 cause Siderius type X-linked mental retardation (XLMR) (OMIM 300263).[4][5][6] 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.[7][8][9] 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.[10]
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,[9] 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.[11] In humans, fetal cleft lip and other congenital abnormalities have also been linked to maternal hypoxia, as caused by e.g. maternal smoking,[12] maternal alcohol abuse or maternal hypertension treatment.[13]
References
- ^ "Entrez Gene: PHF8 PHD finger protein 8".
- ^ Loenarz, C.; Schofield, C. J. (2008). "Expanding chemical biology of 2-oxoglutarate oxygenases". Nat. Chem. Biol. 4 (3): 152–156. doi:10.1038/nchembio0308-152. PMID 18277970.
- ^ a b c Loenarz, C.; Ge W., Coleman M. L., Rose N. R., Cooper C. D. O., Klose R. J., Ratcliffe P. J., Schofield, C. J. (2009). "PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an N{varepsilon}-dimethyl lysine demethylase". Hum. Mol. Genet. 19 (2): 217–22. doi:10.1093/hmg/ddp480. PMID 19843542.
- ^ Siderius LE, Hamel BC, van Bokhoven H et al. (2000). "X-linked mental retardation associated with cleft lip/palate maps to Xp11.3-q21.3.". Am. J. Med. Genet. 85 (3): 216–220. doi:10.1002/(SICI)1096-8628(19990730)85:3<216::AID-AJMG6>3.0.CO;2-X. PMID 10398231.
- ^ "OMIM: Siderius X-linked mental retardation syndrome". Retrieved 2009-10-21.
- ^ "OMIM: PHD finger protein 8; PHF8". Retrieved 2009-10-21.
- ^ Abidi, F. E.; Miano, M. G.; Murray, J. C.; Schwartz, C. E. (2007). "A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate". Clin. Genet. 72 (1): 19–22. doi:10.1111/j.1399-0004.2007.00817.x. PMC 2570350. PMID 17594395.
- ^ Laumonnier F, Holbert S, Ronce N et al. (2006). "Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate.". J. Med. Genet. 42 (10): 780–786. doi:10.1136/jmg.2004.029439. PMC 1735927. PMID 16199551.
- ^ a b Koivisto AM, Ala-Mello S, Lemmelä S et al. (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.". Clin. Genet. 72 (2): 145–149. doi:10.1111/j.1399-0004.2007.00836.x. PMID 17661819.
- ^ Qiao, Y; Liu, X.; Harvard, C.; Hildebrand, M. J.; Rajcan-Separovic, E.; Holden, J. J. A.; Lewis, M. E. S. (2008). "Autism-associated familial microdeletion of Xp11.22". Clin. Genet. 74 (2): 134–144. doi:10.1111/j.1399-0004.2008.01028.x. PMID 18498374.
- ^ Millicovsky, G.; Johnston, M.C. (1981). "Hyperoxia and hypoxia in pregnancy: simple experimental manipulation alters the incidence of cleft lip and palate in CL/Fr mice". Proc. Natl. Acad. Sci. U.S.A. 78 (9): 5722–5723. doi:10.1073/pnas.78.9.5722. PMC 348841. PMID 6946511.
- ^ Shi, M.; Wehby, G.L. and Murray, J.C. (2008). "Review on genetic variants and maternal smoking in the etiology of oral clefts and other birth defects". Birth Defects Res., Part C 84 (1): 16–29. doi:10.1002/bdrc.20117. PMC 2570345. PMID 18383123.
- ^ Hurst, J. A.; Houlston, R.S., Roberts, A., Gould, S.J. and Tingey, W.G. (1995). "Transverse limb deficiency, facial clefting and hypoxic renal damage: an association with treatment of maternal hypertension?". Clin. Dysmorphol. 4 (4): 359–363. doi:10.1097/00019605-199510000-00013. PMID 8574428.
Further reading
- Ross MT, Grafham DV, Coffey AJ et al. (2005). "The DNA sequence of the human X chromosome.". Nature 434 (7031): 325–337. doi:10.1038/nature03440. PMC 2665286. PMID 15772651.
External links
- PHF8 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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