Plant homeodomain finger protein 6 (PHF6) is a chromatin adaptor protein structurally defined by its two zinc-knuckle-atypical PHD (ZaP) domains. This structural configuration mediates its interaction with dsDNA, miRNA, the nucleosome remodeling and deacetylase (NuRD) complex and regulators of rDNA transcription (Upstream binding factor (UBF) and RNA polymerase-associated factor 1 complex (Paf1C)), ultimately facilitating its role as a chromatin adaptor protein and regulator of gene expression. Mutations in the gene are implicated in Börjeson–Forssman–Lehmann syndrome (BFLS), a rare X-linked intellectual disability disorder characterized by large ears, truncal obesity, and long tapering fingers. BFLS is primarily caused by missense and nonsense mutations while deletions, frameshifts and mutations disrupting the structural integrity of the ZaP domains have been described in T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) patients. To provide more insight into PHF6 and BFLS, we have generated a Phf6 transgenic mouse line with a patient-related nonsense mutation (R342X). We show that the mutation drastically reduced Phf6 transcript levels and produced a truncated protein at very low levels in the developing brain. Mice were born at normal Mendelian ratios but mutant mice were significantly smaller than control littermates. Volumetric analysis of the brain via high resolution MRI revealed increased sizes of the amygdala, periaqueductal gray, and hypothalamus, and decreased volumes within the striatum, hippocampus and cerebellum. Studies of the pituitary gland revealed a postnatal defect in the growth of the anterior pituitary but not the posterior or intermediate regions. This change was reflected in altered expression levels of several hormones in the hypothalamic-pituitary-adrenal axis. Preliminary behavioral tests highlighted deficits in the anxiety and depression response of the mutant mice. Additional studies to fully characterize these mice are ongoing.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/38848 |
| Date | 26 February 2019 |
| Creators | Ahmed, Raies |
| Contributors | Picketts, David |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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