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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome
American Journal of Human Genetics, Volume 77, No. 2, Year 2005
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Description
The expression of a gene requires not only a normal coding sequence but also intact regulatory regions, which can be located at large distances from the target genes, as demonstrated for an increasing number of developmental genes. In previous mutation studies of the role of FOXL2 in blepharophimosis syndrome (BPES), we identified intragenic mutations in 70% of our patients. Three translocation breakpoints upstream of FOXL2 in patients with BPES suggested a position effect. Here, we identified novel microdeletions outside of FOXL2 in cases of sporadic and familial BPES. Specifically, four rearrangements, with an overlap of 126 kb, are located 230 kb upstream of FOXL2, telomeric to the reported translocation breakpoints. Moreover, the shortest region of deletion overlap (SRO) contains several conserved nongenic sequences (CNGs) harboring putative transcription-factor binding sites and representing potential long-range cis-regulatory elements. Interestingly, the human region orthologous to the 12-kb sequence deleted in the polled intersex syndrome in goat, which is an animal model for BPES, is contained in this SRO, providing evidence of human-goat conservation of FOXL2 expression and of the mutational mechanism. Surprisingly, in a fifth family with BPES, one rearrangement was found downstream of FOXL2. In addition, we report nine novel rearrangements encompassing FOXL2 that range from partial gene deletions to submicroscopic deletions. Overall, genomic rearrangements encompassing or outside of FOXL2 account for 16% of all molecular defects found in our families with BPES. In summary, this is the first report of extragenic deletions in BPES, providing further evidence of potential long-range cis-regulatory elements regulating FOXL2 expression. It contributes to the enlarging group of developmental diseases caused by defective distant regulation of gene expression. Finally, we demonstrate that CNGs are candidate regions for genomic rearrangements in developmental genes. © 2005 by The American Society of Human Genetics. All rights reserved.
Authors & Co-Authors
Beysen, Diane
Belgium, Ghent
Universitair Ziekenhuis Gent
Raes, Jeroen
Belgium, Ghent
Universiteit Gent
Leroy, Bart Peter
Belgium, Ghent
Universitair Ziekenhuis Gent
Lucassen, A. M.
United Kingdom, Southampton
University of Southampton
Yates, John R.W.
United Kingdom, Cambridge
Addenbrooke's Hospital
Clayton-Smith, Jill
United Kingdom, London
St Mary's Hospital
Brooks, Susan Sklower
United States, New York
New York State Institute for Basic Research in Developmental Disabilities
Fellous, Marc
France, Paris
Inserm
Fryns, Jean Pierré
Belgium, Leuven
Center for Human Genetics
Lapunzina-Badía, Pablo Daniel
Spain, Madrid
Hospital Universitario la Paz
Lemyre, Emmanuelle
Canada, Montreal
University of Montreal
Meire, Fraņcoise M.
Belgium, Ghent
Universiteit Gent
Messiaen, Ludwine M.
United States, Birmingham
The University of Alabama at Birmingham
Oley, Christine A.
United Kingdom, Birmingham
Birmingham Women's Hospital
Splitt, Miranda Penman
United Kingdom, London
Guy's and st Thomas' Nhs Foundation Trust
Van de Peer, Y.
Belgium, Ghent
Universiteit Gent
Veitia, Reiner Albert
France, Paris
Inserm
de Paepe, Anne M.
Belgium, Ghent
Universitair Ziekenhuis Gent
de Baere, Elfride B.W.
Belgium, Ghent
Universitair Ziekenhuis Gent
Statistics
Citations: 114
Authors: 19
Affiliations: 16
Identifiers
Doi:
10.1086/432083
ISSN:
00029297
Research Areas
Cancer
Genetics And Genomics