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      Comprehensive analysis of the transcriptional landscape of the human FMR1 gene reveals two new long noncoding RNAs differentially expressed in Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome

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          Abstract

          The majority of the human genome is transcribed but not translated, giving rise to noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs, >200 nt) that perform a wide range of functions in gene regulation. The Fragile X mental retardation 1 ( FMR1) gene is a microsatellite locus that in the general population contains <55 CGG repeats in its 5′-untranslated region. Expansion of this repeat region to a size of 55-200 CGG repeats, known as premutation, is associated with Fragile X tremor and ataxia syndrome (FXTAS). Further expansion beyond 200 CGG repeats, or full mutation, leads to FMR1 gene silencing and results in Fragile X syndrome (FXS). Using a novel technology called “Deep-RACE”, which combines rapid amplification of cDNA ends (RACE) with next generation sequencing, we systematically interrogated the FMR1 gene locus for the occurrence of novel lncRNAs. We discovered two transcripts, FMR5 and FMR6. FMR5 is a sense lncRNA transcribed upstream of the FMR1 promoter, whereas FMR6 is an antisense transcript overlapping the 3′ region of FMR1. FMR5 was expressed in several human brain regions from unaffected individuals and from full and premutation patients. FMR6 was silenced in full mutation and, unexpectedly, in premutation carriers suggesting abnormal transcription and/or chromatin remodeling prior to transition to the full mutation. These lncRNAs may thus be useful as biomarkers, allowing for early detection and therapeutic intervention in FXS and FXTAS. Finally we show that FMR5 and FMR6 are expressed in peripheral blood leukocytes and propose future studies that correlate lncRNA expression with clinical outcomes.

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          The online version of this article (doi:10.1007/s00439-013-1356-6) contains supplementary material, which is available to authorized users.

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          Most cited references37

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          Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript.

          Alternative promoters within the same gene are a general phenomenon in gene expression. Mechanisms of their selective regulation vary from one gene to another and are still poorly understood. Here we show that in quiescent cells the mechanism of transcriptional repression of the major promoter of the gene encoding dihydrofolate reductase depends on a non-coding transcript initiated from the upstream minor promoter and involves both the direct interaction of the RNA and promoter-specific interference. The specificity and efficiency of repression is ensured by the formation of a stable complex between non-coding RNA and the major promoter, direct interaction of the non-coding RNA with the general transcription factor IIB and dissociation of the preinitiation complex from the major promoter. By using in vivo and in vitro assays such as inducible and reconstituted transcription, RNA bandshifts, RNA interference, chromatin immunoprecipitation and RNA immunoprecipitation, we show that the regulatory transcript produced from the minor promoter has a critical function in an epigenetic mechanism of promoter-specific transcriptional repression.
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            CDART: protein homology by domain architecture.

            The Conserved Domain Architecture Retrieval Tool (CDART) performs similarity searches of the NCBI Entrez Protein Database based on domain architecture, defined as the sequential order of conserved domains in proteins. The algorithm finds protein similarities across significant evolutionary distances using sensitive protein domain profiles rather than by direct sequence similarity. Proteins similar to a query protein are grouped and scored by architecture. Relying on domain profiles allows CDART to be fast, and, because it relies on annotated functional domains, informative. Domain profiles are derived from several collections of domain definitions that include functional annotation. Searches can be further refined by taxonomy and by selecting domains of interest. CDART is available at http://www.ncbi.nlm.nih.gov/Structure/lexington/lexington.cgi.
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              Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.

              The authors report five elderly men with the fragile X premutation who had a progressive action tremor associated with executive function deficits and generalized brain atrophy. These individuals had elevated fragile X mental retardation 1 gene (FMR1) messenger RNA and normal or borderline levels of FMR1 protein. The authors propose that elevations of FMR1 messenger RNA may be causative for a neurodegenerative syndrome in a subgroup of elderly men with the FMR1 premutation.
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                Author and article information

                Contributors
                cpastori@med.miami.edu
                cwahlestedt@med.miami.edu
                Journal
                Hum Genet
                Hum. Genet
                Human Genetics
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0340-6717
                1432-1203
                5 September 2013
                5 September 2013
                2014
                : 133
                : 59-67
                Affiliations
                [ ]Department of Psychiatry and Behavioral Sciences and Center for Therapeutic Innovation, Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 33136 USA
                [ ]Division of Clinical and Translational Genetics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL 33136 USA
                [ ]Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 33136 USA
                Article
                1356
                10.1007/s00439-013-1356-6
                3898532
                24005575
                2aa89ea2-2dc9-491b-a068-3a42425755a4
                © The Author(s) 2013

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                : 28 May 2013
                : 25 August 2013
                Categories
                Original Investigation
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2014

                Genetics
                Genetics

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