Screening of mutations in the PHF8 gene and identification of a novel mutation in a Finnish family with XLMR and cleft lip/cleft palate

Abstract

We investigated the prevalence of mutations in the PHD finger protein 8 (PHF8) gene in X‐linked mental retardation (XLMR) and facial cleft starting from the original cohort of 7712 patients operated on since1 January 1950 for cleft lip/cleft palate in the Cleft Centre at the Helsinki University Hospital. From this nationwide material, 18 patients including one family with two male patients with cleft lip/cleft palate and unknown cause of mental retardation (MR) were sequenced for the coding regions and splice sites of the PHF8 gene. A novel missense mutation c.836C>T of the PHF8 gene was identified in a Finnish family with multiple‐affected male patients. The mutation resides in exon 8 and changes phenylalanine to serine (F279S) in the functionally important Jmonji C domain of the protein. The clinical phenotype of the male patients was characterized by mild MR, mild dysmorphic features, unilateral cleft lip and cleft palate in one and bilateral cleft lip and cleft palate in the other sibling. The mutation was not present in 200 anonymous blood donors (approximately 300 X‐chromosomes). To our knowledge, F279S is the third mutation of the PHF8 gene identified so far.

Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

“…PHF8 was previously identified to demethylate mono-and dimethylated histone H3K9 and monomethylated histone H3K20 (Horton et al, 2010;Loenarz et al, 2010;Qi et al, 2010). Inactivating mutations in the PHF8 JmjCdomain are linked to mental retardation syndromes with the cleft lip/palate (Laumonnier et al, 2005;Abidi et al, 2007;Koivisto et al, 2007;Qiao et al, 2008). This may be because of critical transcriptional co-activator functions of PHF8 in the regulation of neuronal and craniofacial development (Fortschegger et al, 2010;Kleine-Kohlbrecher et al, 2010;Qi et al, 2010).…”

The X-linked mental retardation gene PHF8 is a histone demethylase involved in neuronal differentiation

“…Here we show that PHF8 is a histone demethylase, and importantly, an F279S mutant identified in PHF8 from a family of XLMR patients is deficient in enzymatic activity [17]. In addition, we show that PHF8 interacts with and functions as a coactivator for retinoic acid receptor (RAR).…”

“…PHF8 is an X-linked gene encoding an evolutionarily conserved protein containing an N-terminal PHD (plant homeodomain) domain and a JmjC domain, the latter being a signature of JmjC family histone demethylases. Nonsense and missense mutations in PHF8 have been causally linked with X-linked mental retardation (XLMR) with cleft lip/cleft palate [16,17]. However, the underlying mechanism is not known.…”

“…PHF8 has recently been shown to be a causal gene for XLMR and cleft lip/cleft palate [16,17]. While most PHF8 mutations identified so far in patients are nonsense mutations that result in truncation of a large portion of the protein, one mutation (836T-C) changes phenylalanine at amino acid position 279 in the HeLa nuclear extracts were incubated with various C-terminal biotinylated histone H3 peptides (aa1-26, 1 µg) that were pre-bound to streptavidin-agarose beads.…”

“…The binding of His-PHF8(aa1-428) was detected by Coomassie blue staining. JmjC domain to serine [17]. To test whether PHF8 enzymatic activity is causally linked to the disease, we examined whether the F279S mutation affects PHF8 enzymatic activity.…”