Duplications Involving a Conserved Regulatory Element Downstream of BMP2 Are Associated with Brachydactyly Type A2
Autor(a) principal: | |
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Data de Publicação: | 2009 |
Outros Autores: | , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | http://repositorio.unifesp.br/handle/11600/31453 http://dx.doi.org/10.1016/j.ajhg.2009.03.001 |
Resumo: | Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers, has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5). A linkage analysis performed in a mutation-negative family identified a novel locus for BDA2 on chromosome 20p12.3 that incorporates the gene for Bone morphogenetic protein 2 (BMP2). No point mutation was identified in BMP2, so a high-density array CGH analysis covering the critical interval of similar to 1.3 Mb was performed. A microduplication of: similar to 5.5 kb in a noncoding sequence similar to 110 kb downstream of BMP2 was detected. Screening of other patients by qPCR revealed a similar duplication in a second family. the duplicated region contains evolutionary highly conserved sequences suggestive of a long-range regulator. By using a transgenic mouse model we can show that this sequence is able to drive expression of a X-Gal reporter construct in the limbs. the almost complete overlap with endogenous Bmp2 expression indicates that a limb-specific enhancer of Bmp2 is located within the identified duplication. Our results reveal an additional functional mechanism for the pathogenesis of BDA2, which is duplication of a regulatory element that affects the expression of BMP2 in the developing limb. |
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Dathe, KatarinaKjaer, Klaus W.Brehm, AnjaMeinecke, PeterNuernberg, PeterCorrêa Neto, Jordão [UNIFESP]Brunoni, Decio [UNIFESP]Tommerup, NilsOtt, Claus E.Klopocki, EvaSeemann, PetraMundlos, StefanCharite Univ Med BerlinUniv CopenhagenMax Planck Inst Mol GenetFree Univ BerlinAltonaer KinderkrankenhausUniv CologneUniversidade Federal de São Paulo (UNIFESP)Berlin Brandenburg Ctr Regenerat Therapies BCRT2016-01-24T13:52:26Z2016-01-24T13:52:26Z2009-04-10American Journal of Human Genetics. Cambridge: Cell Press, v. 84, n. 4, p. 483-492, 2009.0002-9297http://repositorio.unifesp.br/handle/11600/31453http://dx.doi.org/10.1016/j.ajhg.2009.03.001WOS000265232800007.pdf10.1016/j.ajhg.2009.03.001WOS:000265232800007Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers, has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5). A linkage analysis performed in a mutation-negative family identified a novel locus for BDA2 on chromosome 20p12.3 that incorporates the gene for Bone morphogenetic protein 2 (BMP2). No point mutation was identified in BMP2, so a high-density array CGH analysis covering the critical interval of similar to 1.3 Mb was performed. A microduplication of: similar to 5.5 kb in a noncoding sequence similar to 110 kb downstream of BMP2 was detected. Screening of other patients by qPCR revealed a similar duplication in a second family. the duplicated region contains evolutionary highly conserved sequences suggestive of a long-range regulator. By using a transgenic mouse model we can show that this sequence is able to drive expression of a X-Gal reporter construct in the limbs. the almost complete overlap with endogenous Bmp2 expression indicates that a limb-specific enhancer of Bmp2 is located within the identified duplication. Our results reveal an additional functional mechanism for the pathogenesis of BDA2, which is duplication of a regulatory element that affects the expression of BMP2 in the developing limb.DFGSFBDanish National Research Foundation.Charite Univ Med Berlin, Inst Med Genet, D-13353 Berlin, GermanyUniv Copenhagen, Inst Cellular & Mol Med, Wilhelm Johannsen Ctr Funct Genome Res, DK-2200 Copenhagen, DenmarkMax Planck Inst Mol Genet, D-14195 Berlin, GermanyFree Univ Berlin, Inst Biochem, D-14195 Berlin, GermanyAltonaer Kinderkrankenhaus, Abt Med Genet, D-22763 Hamburg, GermanyUniv Cologne, Inst Genet, D-50674 Cologne, GermanyUniv Cologne, Cologne Ctr Genom, D-50674 Cologne, GermanyUniv Cologne, Ctr Mol Med Cologne, D-50931 Cologne, GermanyUniversidade Federal de São Paulo, Ctr Genet Med, BR-04023062 São Paulo, BrazilBerlin Brandenburg Ctr Regenerat Therapies BCRT, D-13353 Berlin, GermanyUniversidade Federal de São Paulo, Ctr Genet Med, BR-04023062 São Paulo, BrazilDFG: LE1851/1-2SFB: 760Web of Science483-492engCell PressAmerican Journal of Human GeneticsDuplications Involving a Conserved Regulatory Element Downstream of BMP2 Are Associated with Brachydactyly Type A2info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESPORIGINALWOS000265232800007.pdfapplication/pdf1014134${dspace.ui.url}/bitstream/11600/31453/1/WOS000265232800007.pdf2ccfa3a0003adc79867d39f1437c09f5MD51open accessTEXTWOS000265232800007.pdf.txtWOS000265232800007.pdf.txtExtracted texttext/plain44335${dspace.ui.url}/bitstream/11600/31453/2/WOS000265232800007.pdf.txt7c5a30be0e71bebb3b1208ddf8ddf141MD52open access11600/314532022-09-27 12:00:35.718open accessoai:repositorio.unifesp.br:11600/31453Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652023-05-25T12:26:07.034488Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Duplications Involving a Conserved Regulatory Element Downstream of BMP2 Are Associated with Brachydactyly Type A2 |
title |
Duplications Involving a Conserved Regulatory Element Downstream of BMP2 Are Associated with Brachydactyly Type A2 |
spellingShingle |
Duplications Involving a Conserved Regulatory Element Downstream of BMP2 Are Associated with Brachydactyly Type A2 Dathe, Katarina |
title_short |
Duplications Involving a Conserved Regulatory Element Downstream of BMP2 Are Associated with Brachydactyly Type A2 |
title_full |
Duplications Involving a Conserved Regulatory Element Downstream of BMP2 Are Associated with Brachydactyly Type A2 |
title_fullStr |
Duplications Involving a Conserved Regulatory Element Downstream of BMP2 Are Associated with Brachydactyly Type A2 |
title_full_unstemmed |
Duplications Involving a Conserved Regulatory Element Downstream of BMP2 Are Associated with Brachydactyly Type A2 |
title_sort |
Duplications Involving a Conserved Regulatory Element Downstream of BMP2 Are Associated with Brachydactyly Type A2 |
author |
Dathe, Katarina |
author_facet |
Dathe, Katarina Kjaer, Klaus W. Brehm, Anja Meinecke, Peter Nuernberg, Peter Corrêa Neto, Jordão [UNIFESP] Brunoni, Decio [UNIFESP] Tommerup, Nils Ott, Claus E. Klopocki, Eva Seemann, Petra Mundlos, Stefan |
author_role |
author |
author2 |
Kjaer, Klaus W. Brehm, Anja Meinecke, Peter Nuernberg, Peter Corrêa Neto, Jordão [UNIFESP] Brunoni, Decio [UNIFESP] Tommerup, Nils Ott, Claus E. Klopocki, Eva Seemann, Petra Mundlos, Stefan |
author2_role |
author author author author author author author author author author author |
dc.contributor.institution.none.fl_str_mv |
Charite Univ Med Berlin Univ Copenhagen Max Planck Inst Mol Genet Free Univ Berlin Altonaer Kinderkrankenhaus Univ Cologne Universidade Federal de São Paulo (UNIFESP) Berlin Brandenburg Ctr Regenerat Therapies BCRT |
dc.contributor.author.fl_str_mv |
Dathe, Katarina Kjaer, Klaus W. Brehm, Anja Meinecke, Peter Nuernberg, Peter Corrêa Neto, Jordão [UNIFESP] Brunoni, Decio [UNIFESP] Tommerup, Nils Ott, Claus E. Klopocki, Eva Seemann, Petra Mundlos, Stefan |
description |
Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers, has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5). A linkage analysis performed in a mutation-negative family identified a novel locus for BDA2 on chromosome 20p12.3 that incorporates the gene for Bone morphogenetic protein 2 (BMP2). No point mutation was identified in BMP2, so a high-density array CGH analysis covering the critical interval of similar to 1.3 Mb was performed. A microduplication of: similar to 5.5 kb in a noncoding sequence similar to 110 kb downstream of BMP2 was detected. Screening of other patients by qPCR revealed a similar duplication in a second family. the duplicated region contains evolutionary highly conserved sequences suggestive of a long-range regulator. By using a transgenic mouse model we can show that this sequence is able to drive expression of a X-Gal reporter construct in the limbs. the almost complete overlap with endogenous Bmp2 expression indicates that a limb-specific enhancer of Bmp2 is located within the identified duplication. Our results reveal an additional functional mechanism for the pathogenesis of BDA2, which is duplication of a regulatory element that affects the expression of BMP2 in the developing limb. |
publishDate |
2009 |
dc.date.issued.fl_str_mv |
2009-04-10 |
dc.date.accessioned.fl_str_mv |
2016-01-24T13:52:26Z |
dc.date.available.fl_str_mv |
2016-01-24T13:52:26Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
American Journal of Human Genetics. Cambridge: Cell Press, v. 84, n. 4, p. 483-492, 2009. |
dc.identifier.uri.fl_str_mv |
http://repositorio.unifesp.br/handle/11600/31453 http://dx.doi.org/10.1016/j.ajhg.2009.03.001 |
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0002-9297 |
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WOS000265232800007.pdf |
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10.1016/j.ajhg.2009.03.001 |
dc.identifier.wos.none.fl_str_mv |
WOS:000265232800007 |
identifier_str_mv |
American Journal of Human Genetics. Cambridge: Cell Press, v. 84, n. 4, p. 483-492, 2009. 0002-9297 WOS000265232800007.pdf 10.1016/j.ajhg.2009.03.001 WOS:000265232800007 |
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http://repositorio.unifesp.br/handle/11600/31453 http://dx.doi.org/10.1016/j.ajhg.2009.03.001 |
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eng |
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Cell Press |
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Cell Press |
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