1. Debrey SM, Leehey MA, Klepitskaya O, Filley CM, Shah RC, Kluger B, Berry-Kravis E, Spector E, Tassone F, Hall DA. {{Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: a Case Series}}. {Cerebellum};2016 (Jul 2)
Considerable research has focused on patients with trinucleotide (CGG) repeat expansions in the fragile X mental retardation 1 (FMR1) gene that fall within either the full mutation (>200 repeats) or premutation range (55-200 repeats). Recent interest in individuals with gray zone expansions (41-54 CGG repeats) has grown due to reported phenotypes that are similar to those observed in premutation carriers, including neurological, molecular, and cognitive signs. The purpose of this manuscript is to describe a series of adults with FMR1 alleles in the gray zone presenting with movement disorders or memory loss. Gray zone carriers ascertained in large FMR1 screening studies were identified and their clinical phenotypes studied. Thirty-one gray zone allele carriers were included, with mean age of symptom onset of 53 years in patients with movement disorders and 57 years in those with memory loss. Four patients were chosen for illustrative case reports and had the following diagnoses: early-onset Parkinson disease (PD), atypical parkinsonism, dementia, and atypical essential tremor. Some gray zone carriers presenting with parkinsonism had typical features, including bradykinesia, rigidity, and a positive response to dopaminergic medication. These patients had a higher prevalence of peripheral neuropathy and psychiatric complaints than would be expected. The patients seen in memory clinics had standard presentations of cognitive impairment with no apparent differences. Further studies are necessary to determine the associations between FMR1 expansions in the gray zone and various phenotypes of neurological dysfunction.
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2. Gross C. {{Defective phosphoinositide metabolism in autism}}. {J Neurosci Res};2016 (Jul 4)
Phosphoinositides are essential components of lipid membranes and crucial regulators of many cellular functions, including signal transduction, vesicle trafficking, membrane receptor localization and activity, and determination of membrane identity. These functions depend on the dynamic and highly regulated metabolism of phosphoinositides and require finely balanced activity of specific phosphoinositide kinases and phosphatases. There is increasing evidence from genetic and functional studies that these enzymes are often dysregulated or mutated in autism spectrum disorders; in particular, phosphoinositide 3-kinases and their regulatory subunits appear to be affected frequently. Examples of autism spectrum disorders with defective phosphoinositide metabolism are fragile X syndrome and autism disorders associated with mutations in the phosphoinositide 3-phosphatase tensin homolog deleted on chromosome 10 (PTEN), but recent genetic analyses also suggest that select nonsyndromic, idiopathic forms of autism may have altered activity of phosphoinositide kinases and phosphatases. Isoform-specific inhibitors for some of the phosphoinositide kinases have already been developed for cancer research and treatment, and a few are being evaluated for use in humans. Altogether, this offers exciting opportunities to explore altered phosphoinositide metabolism as a therapeutic target in individuals with certain forms of autism. This review summarizes genetic and functional studies identifying defects in phosphoinositide metabolism in autism and related disorders, describes published preclinical work targeting phosphoinositide 3-kinases in neurological diseases, and discusses the opportunities and challenges ahead to translate these findings from animal models and human cells into clinical application in humans. (c) 2016 Wiley Periodicals, Inc.
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3. Kumari D, Usdin K. {{Sustained expression of FMR1 mRNA from reactivated fragile X syndrome alleles after treatment with small molecules that prevent trimethylation of H3K27}}. {Hum Mol Genet};2016 (Jul 4)
Expansion of a CGG-repeat tract in the 5′-untranslated region of the FMR1 gene to >200 repeats results in epigenetic silencing of the gene by a mechanism that is still unknown. FMR1 gene silencing results in fragile X syndrome (FXS), the most common heritable cause of intellectual disability. We have previously shown that reactivation of FMR1 gene in FXS cells with 5-azadeoxycytidine (AZA) leads to the transient recruitment of EZH2, the polycomb repressive complex 2 (PRC2) component responsible for H3K27 trimethylation, and that this recruitment depends on the presence of the FMR1 transcript. However, whether H3K27 trimethylation was essential for FMR1 re-silencing was not known. We show here that EZH2 inhibitors increased FMR1 expression and significantly delayed re-silencing of the FMR1 gene in AZA-treated FXS cells. This delay occurred despite the fact that EZH2 inhibition did not prevent the return of DNA methylation. Treatment with compound 1a, a small molecule that targets CGG-repeats in the FMR1 mRNA, also resulted in sustained expression of the FMR1 gene in AZA-treated cells. This effect of 1a was also associated with a decrease in the levels of H3K27 trimethylation but not DNA methylation. Thus, our data show that EZH2 plays a critical role in the FMR1 gene silencing process and that its inhibition can prolong expression of the FMR1 gene even in the presence of its transcript.
