Abidi FE, Miano MG, Murray JC, Schwartz CE.. A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate. Clin Genet 72: 19-22

Center for Molecular Studies, J C Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA.
Clinical Genetics (Impact Factor: 3.93). 08/2007; 72(1):19-22. DOI: 10.1111/j.1399-0004.2007.00817.x
Source: PubMed


Recently, two truncating mutations in the PHF8 (plant homeodomain finger protein 8) gene have been found to cause X-linked mental retardation associated with cleft lip/cleft palate (CL/P). One of the truncating mutations was found in the original family with Siderius-Hamel CL/P syndrome where only two of the three affected individuals had mental retardation (MR) with CL/P and one individual had mild MR. The second mutation was present in a family with four affected men, three of whom had MR and CL/P, while the fourth individual had mild MR without clefting. Here, we report a novel nonsense mutation (p.K177X) in a male patient who has MR associated with CL/P. The mutation results in a truncated PHF8 protein lacking the Jumonji-like C terminus domain and five nuclear localization signals. Our finding further supports the hypothesis that the PHF8 protein may play an important role in cognitive function and midline formation.

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    • "PHF8 preferentially acts on H3K9me2 and H3K9me1 (however, some results also suggest that it can demethylate H4K20me1) and associates with transcriptional activation and retinoic acid signaling pathway in neuronal differentiation (Qiu et al., 2010). Mutations in the PHF8 gene are found in patients with X-linked mental retardation (XLMR), and knockdown of PHF8 homolog leads to brain defects in zebrafish (Abidi et al., 2007; Koivisto et al., 2007; Laumonnier et al., 2005), revealing its potential involvement in human disease. "
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    ABSTRACT: While all-trans retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) has been the paradigm of targeted therapy for oncogenic transcription factors, the underlying mechanisms remain largely unknown, and a significant number of patients still relapse and become ATRA resistant. We identified the histone demethylase PHF8 as a coactivator that is specifically recruited by RARα fusions to activate expression of their downstream targets upon ATRA treatment. Forced expression of PHF8 resensitizes ATRA-resistant APL cells, whereas its downregulation confers resistance. ATRA sensitivity depends on the enzymatic activity and phosphorylation status of PHF8, which can be pharmacologically manipulated to resurrect ATRA sensitivity to resistant cells. These findings provide important molecular insights into ATRA response and a promising avenue for overcoming ATRA resistance.
    Cancer cell 03/2013; 23(3):376-89. DOI:10.1016/j.ccr.2013.02.014 · 23.52 Impact Factor
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    • "These proteins contain an N-terminal PHD and a Jumonji-C (JmjC) domain (7). Deletions and point mutations in the PHF8 JmjC domain lead to Siderius–Hamel syndrome, mild XLMR with cleft lip and/or a cleft palate (CL/P) (4,8–10). "
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    ABSTRACT: PHF8 is a histone demethylase associated with X-linked mental retardation. It has been described as a transcriptional co-activator involved in cell cycle progression, but its physiological role is still poorly understood. Here we show that PHF8 controls the expression of genes involved in cell adhesion and cytoskeleton organization such as RhoA, Rac1 and GSK3β. A lack of PHF8 not only results in a cell cycle delay but also in a disorganized actin cytoskeleton and impaired cell adhesion. Our data demonstrate that PHF8 directly regulates the expression of these genes by demethylating H4K20me1 at promoters. Moreover, c-Myc transcription factor cooperates with PHF8 to regulate the analysed promoters. Further analysis in neurons shows that depletion of PHF8 results in down-regulation of cytoskeleton genes and leads to a deficient neurite outgrowth. Overall, our results suggest that the mental retardation phenotype associated with loss of function of PHF8 could be due to abnormal neuronal connections as a result of alterations in cytoskeleton function.
    Nucleic Acids Research 07/2012; 40(19):9429-40. DOI:10.1093/nar/gks716 · 9.11 Impact Factor
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    • "Mutations in TBX22 have also been identified in patients with isolated CPO [51], [52]. As to PHF8, mutations in this gene cause the X-linked mental retardation syndrome Siderius that includes cleft palate as a common phenotypic feature [53], [54]. PHF8 is a histone lysine transcription activator expected to have a wide range of functions. "
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    ABSTRACT: Orofacial clefts are common birth defects of complex etiology, with an excess of males among babies with cleft lip and palate, and an excess of females among those with cleft palate only. Although genes on the X chromosome have been implicated in clefting, there has been no association analysis of X-linked markers. We added new functionalities in the HAPLIN statistical software to enable association analysis of X-linked markers and an exploration of various causal scenarios relevant to orofacial clefts. Genotypes for 48 SNPs in 18 candidate genes on the X chromosome were analyzed in two population-based samples from Scandinavia (562 Norwegian and 235 Danish case-parent triads). For haplotype analysis, we used a sliding-window approach and assessed isolated cleft lip with or without cleft palate (iCL/P) separately from isolated cleft palate only (iCPO). We tested three statistical models in HAPLIN, allowing for: i) the same relative risk in males and females, ii) sex-specific relative risks, and iii) X-inactivation in females. We found weak but consistent associations with the oral-facial-digital syndrome 1 (OFD1) gene (formerly known as CXORF5) in the Danish iCL/P samples across all models, but not in the Norwegian iCL/P samples. In sex-specific analyses, the association with OFD1 was in male cases only. No analyses showed associations with iCPO in either the Norwegian or the Danish sample. The association of OFD1 with iCL/P is plausible given the biological relevance of this gene. However, the lack of replication in the Norwegian samples highlights the need to verify these preliminary findings in other large datasets. More generally, the novel analytic methods presented here are widely applicable to investigations of the role of X-linked genes in complex traits.
    PLoS ONE 06/2012; 7(6):e39240. DOI:10.1371/journal.pone.0039240 · 3.23 Impact Factor
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