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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

Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome
Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome
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.
0002-9297
205-218
Beysen, D.
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Raes, J.
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Leroy, B. P.
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Lucassen, A.
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Yates, J. R.
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Clayton-Smith, J.
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Ilyina, H.
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Brooks, S. S.
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Christin-Maitre, S.
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Fellous, M.
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Fryns, J. P.
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Kim, J. R.
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Lapunzina, P.
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Lemyre, E.
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Meire, F.
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Messiaen, L. M.
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Oley, C.
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Splitt, M.
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Thomson, J.
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Peer, Y. V.
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Veitia, R. A.
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De Paepe, A.
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De Baere, E.
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Beysen, D.
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Raes, J.
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Leroy, B. P.
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Lucassen, A.
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Yates, J. R.
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Clayton-Smith, J.
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Ilyina, H.
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Brooks, S. S.
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Christin-Maitre, S.
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Fellous, M.
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Fryns, J. P.
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Kim, J. R.
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Lapunzina, P.
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Lemyre, E.
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Meire, F.
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Messiaen, L. M.
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Oley, C.
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Splitt, M.
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Thomson, J.
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Peer, Y. V.
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Veitia, R. A.
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De Paepe, A.
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De Baere, E.
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Beysen, D., Raes, J., Leroy, B. P., Lucassen, A., Yates, J. R., Clayton-Smith, J., Ilyina, H., Brooks, S. S., Christin-Maitre, S., Fellous, M., Fryns, J. P., Kim, J. R., Lapunzina, P., Lemyre, E., Meire, F., Messiaen, L. M., Oley, C., Splitt, M., Thomson, J., Peer, Y. V., Veitia, R. A., De Paepe, A. and De Baere, E. (2005) Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome. The American Journal of Human Genetics, 77 (2), 205-218. (doi:10.1086/432083).

Record type: Article

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.

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Published date: 2005

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Local EPrints ID: 26218
URI: http://eprints.soton.ac.uk/id/eprint/26218
ISSN: 0002-9297
PURE UUID: 8508ca3a-78bd-4bc2-a0fe-42d116211dee

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Date deposited: 07 Apr 2006
Last modified: 09 Dec 2019 19:09

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Contributors

Author: D. Beysen
Author: J. Raes
Author: B. P. Leroy
Author: A. Lucassen
Author: J. R. Yates
Author: J. Clayton-Smith
Author: H. Ilyina
Author: S. S. Brooks
Author: S. Christin-Maitre
Author: M. Fellous
Author: J. P. Fryns
Author: J. R. Kim
Author: P. Lapunzina
Author: E. Lemyre
Author: F. Meire
Author: L. M. Messiaen
Author: C. Oley
Author: M. Splitt
Author: J. Thomson
Author: Y. V. Peer
Author: R. A. Veitia
Author: A. De Paepe
Author: E. De Baere

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