Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening.
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 involvemen...
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Public Library of Science (PLoS)
2009-06-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1000522&type=printable |
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| author | Barbara D'haene Catia Attanasio Diane Beysen Josée Dostie Edmond Lemire Philippe Bouchard Michael Field Kristie Jones Birgit Lorenz Björn Menten Karen Buysse Filip Pattyn Marc Friedli Catherine Ucla Colette Rossier Carine Wyss Frank Speleman Anne De Paepe Job Dekker Stylianos E Antonarakis Elfride De Baere |
| author_facet | Barbara D'haene Catia Attanasio Diane Beysen Josée Dostie Edmond Lemire Philippe Bouchard Michael Field Kristie Jones Birgit Lorenz Björn Menten Karen Buysse Filip Pattyn Marc Friedli Catherine Ucla Colette Rossier Carine Wyss Frank Speleman Anne De Paepe Job Dekker Stylianos E Antonarakis Elfride De Baere |
| author_sort | Barbara D'haene |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ae6f29c6be8c46bf9b53ff13a30398fb |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2009-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-ae6f29c6be8c46bf9b53ff13a30398fb2025-08-20T02:17:24ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042009-06-0156e100052210.1371/journal.pgen.1000522Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening.Barbara D'haeneCatia AttanasioDiane BeysenJosée DostieEdmond LemirePhilippe BouchardMichael FieldKristie JonesBirgit LorenzBjörn MentenKaren BuysseFilip PattynMarc FriedliCatherine UclaColette RossierCarine WyssFrank SpelemanAnne De PaepeJob DekkerStylianos E AntonarakisElfride De BaereTo 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1000522&type=printable |
| spellingShingle | Barbara D'haene Catia Attanasio Diane Beysen Josée Dostie Edmond Lemire Philippe Bouchard Michael Field Kristie Jones Birgit Lorenz Björn Menten Karen Buysse Filip Pattyn Marc Friedli Catherine Ucla Colette Rossier Carine Wyss Frank Speleman Anne De Paepe Job Dekker Stylianos E Antonarakis Elfride De Baere 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 Genetics |
| title | Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening. |
| title_full | Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening. |
| title_fullStr | Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening. |
| title_full_unstemmed | Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening. |
| title_short | Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening. |
| title_sort | disease causing 7 4 kb cis regulatory deletion disrupting conserved non coding sequences and their interaction with the foxl2 promotor implications for mutation screening |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1000522&type=printable |
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