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.
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.
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Barbara
authors: B
authors: D'haene
authors: Catia
authors: C
authors: Attanasio
authors: Diane
authors: D
authors: Beysen
authors: Josée
authors: J
authors: Dostie
authors: Edmond
authors: E
authors: Lemire
authors: Philippe
authors: P
authors: Bouchard
authors: Michael
authors: M
authors: Field
authors: Kristie
authors: K
authors: Jones
authors: Birgit
authors: B
authors: Lorenz
authors: Björn
authors: B
authors: Menten
authors: Karen
authors: K
authors: Buysse
authors: Filip
authors: F
authors: Pattyn
authors: Marc
authors: M
authors: Friedli
authors: Catherine
authors: C
authors: Ucla
authors: Colette
authors: C
authors: Rossier
authors: Carine
authors: C
authors: Wyss
authors: Frank
authors: F
authors: Speleman
authors: Anne
authors: A
authors: De Paepe
authors: Job
authors: J
authors: Dekker
authors: Stylianos E
authors: SE
authors: Antonarakis
authors: Elfride
authors: E
authors: De Baere
mesh_terms: D020121:5' Untranslated Regions; D016569:Blepharophimosis / Q000235:genetics*; D002460:Cell Line; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid; D017384:Sequence Deletion
chemical_list: D020121:5' Untranslated Regions; C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors