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Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in Blepharophimosis syndrome

Diane Beysen, Jeroen Raes UGent, Bart Leroy UGent, A Lucassen, JRW Yates, J Clayton-Smith, H Ilyina, SS Brooks, S Christin-Maitre and Marc Fellous, et al. (2005) AMERICAN JOURNAL OF HUMAN GENETICS. 77(2). p.205-218
abstract
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
EPICANTHUS INVERSUS SYNDROME, PTOSIS, IDENTIFICATION, TRANSLOCATION, MUTATIONS, GENE-EXPRESSION, HUMAN GENOME, BPES, TRANSCRIPTION FACTOR FOXL2, PREMATURE OVARIAN FAILURE
journal title
AMERICAN JOURNAL OF HUMAN GENETICS
Am. J. Hum. Genet.
volume
77
issue
2
pages
205 - 218
Web of Science type
Article
Web of Science id
000230387200003
JCR category
GENETICS & HEREDITY
JCR impact factor
12.649 (2005)
JCR rank
6/119 (2005)
JCR quartile
1 (2005)
ISSN
0002-9297
DOI
10.1086/432083
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
327512
handle
http://hdl.handle.net/1854/LU-327512
date created
2006-03-08 15:21:00
date last changed
2015-06-17 10:33:25
@article{327512,
  abstract     = {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.},
  author       = {Beysen, Diane and Raes, Jeroen and Leroy, Bart and Lucassen, A and Yates, JRW and Clayton-Smith, J and Ilyina, H and Brooks, SS and Christin-Maitre, S and Fellous, Marc and Fryns, Jean-Pierre and Kim, JR and Lapunzina, P and Lemyre, E and Meire, Fran\c{c}oise and Messiaen, Ludwine and Oley, C and Splitt, M and Thomson, J and Van de Peer, Yves and Veitia, RA and De Paepe, Anne and De Baere, Elfride},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keyword      = {EPICANTHUS INVERSUS SYNDROME,PTOSIS,IDENTIFICATION,TRANSLOCATION,MUTATIONS,GENE-EXPRESSION,HUMAN GENOME,BPES,TRANSCRIPTION FACTOR FOXL2,PREMATURE OVARIAN FAILURE},
  language     = {eng},
  number       = {2},
  pages        = {205--218},
  title        = {Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in Blepharophimosis syndrome},
  url          = {http://dx.doi.org/10.1086/432083},
  volume       = {77},
  year         = {2005},
}

Chicago
Beysen, Diane, Jeroen Raes, Bart Leroy, A Lucassen, JRW Yates, J Clayton-Smith, H Ilyina, et al. 2005. “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 77 (2): 205–218.
APA
Beysen, D., Raes, J., Leroy, B., Lucassen, A., Yates, J., Clayton-Smith, J., Ilyina, H., et al. (2005). 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, 77(2), 205–218.
Vancouver
1.
Beysen D, Raes J, Leroy B, Lucassen A, Yates J, Clayton-Smith J, et al. 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. 2005;77(2):205–18.
MLA
Beysen, Diane, Jeroen Raes, Bart Leroy, et al. “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 77.2 (2005): 205–218. Print.