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    Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening

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    Authors
    D'haene, Barbara
    Attanasio, Catia
    Beysen, Diane
    Dostie, Josee
    Lemire, Edmond
    Bouchard, Philippe
    Field, Michael
    Jones, Kristie
    Lorenz, Birgit
    Menten, Bjorn
    Buysse, Karen
    Pattyn, Filip
    Friedli, Marc
    Ucla, Catherine
    Rossier, Colette
    Wyss, Carine
    Speleman, Frank
    De Paepe, Anne
    Dekker, Job
    Antonarakis, Stylianos E.
    De Baere, Elfride
    Show allShow less
    UMass Chan Affiliations
    Program in Gene Function and Expression
    Document Type
    Journal Article
    Publication Date
    2009-06-23
    Keywords
    *5' Untranslated Regions
    Blepharophimosis
    Cell Line
    Conserved Sequence
    DNA Mutational Analysis
    Forkhead Transcription Factors
    Humans
    *Promoter Regions, Genetic
    Protein Binding
    *Regulatory Sequences, Nucleic Acid
    *Sequence Deletion
    Genetics and Genomics
    Show allShow less
    
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    Abstract
    To date, the contribution of disrupted potentially cis-regulatory conserved non-coding sequences (CNCs) to human disease is most likely underestimated, as no systematic screens for putative deleterious variations in CNCs have been conducted. As a model for monogenic disease we studied the involvement of genetic changes of CNCs in the cis-regulatory domain of FOXL2 in blepharophimosis syndrome (BPES). Fifty-seven molecularly unsolved BPES patients underwent high-resolution copy number screening and targeted sequencing of CNCs. Apart from three larger distant deletions, a de novo deletion as small as 7.4 kb was found at 283 kb 5' to FOXL2. The deletion appeared to be triggered by an H-DNA-induced double-stranded break (DSB). In addition, it disrupts a novel long non-coding RNA (ncRNA) PISRT1 and 8 CNCs. The regulatory potential of the deleted CNCs was substantiated by in vitro luciferase assays. Interestingly, Chromosome Conformation Capture (3C) of a 625 kb region surrounding FOXL2 in expressing cellular systems revealed physical interactions of three upstream fragments and the FOXL2 core promoter. Importantly, one of these contains the 7.4 kb deleted fragment. Overall, this study revealed the smallest distant deletion causing monogenic disease and impacts upon the concept of mutation screening in human disease and developmental disorders in particular.
    Source

    D'haene B, Attanasio C, Beysen D, Dostie J, Lemire E, et al. (2009) Disease-Causing 7.4 kb Cis-Regulatory Deletion Disrupting Conserved Non-Coding Sequences and Their Interaction with the FOXL2 Promotor: Implications for Mutation Screening. PLoS Genet 5(6): e1000522. doi:10.1371/journal.pgen.1000522. Link to article on publisher's site

    DOI
    10.1371/journal.pgen.1000522
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/44104
    PubMed ID
    19543368
    Related Resources
    Link to Article in PubMed
    Rights

    Copyright: © 2009 D'haene et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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    10.1371/journal.pgen.1000522
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