en
Scientific article
Open access
English

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

Published inPLOS genetics, vol. 5, no. 6, e1000522
Publication date2009
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.

Keywords
  • Blepharophimosis/ genetics
  • Cell Line
  • Conserved Sequence
  • DNA Mutational Analysis
  • Forkhead Transcription Factors/ genetics
  • Humans
  • Promoter Regions, Genetic
  • Protein Binding
  • Regulatory Sequences, Nucleic Acid
  • Sequence Deletion
Citation (ISO format)
D’HAENE, B. et al. Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening. In: PLOS genetics, 2009, vol. 5, n° 6, p. e1000522. doi: 10.1371/journal.pgen.1000522
Main files (1)
Article (Published version)
accessLevelPublic
Identifiers
ISSN of the journal1553-7390
596views
502downloads

Technical informations

Creation07/12/2010 2:36:09 PM
First validation07/12/2010 2:36:09 PM
Update time03/14/2023 3:53:40 PM
Status update03/14/2023 3:53:39 PM
Last indexation01/15/2024 8:47:31 PM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack