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  Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus

Spielmann, M., Brancati, F., Krawitz, P. M., Robinson, P. N., Ibrahim, D. M., Franke, M., et al. (2012). Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus. American Journal of Human Genetics, 91(4), 629-635. doi:10.1016/j.ajhg.2012.08.014.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-F278-D Version Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-F279-B
Genre: Journal Article

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© 2012 The American Society of Human Genetics. Published by Elsevier Inc.
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 Creators:
Spielmann, M.1, Author              
Brancati, F., Author
Krawitz, P. M., Author
Robinson, P. N.1, Author              
Ibrahim, D. M., Author
Franke, M.1, Author              
Hecht, J.1, Author              
Lohan, S., Author
Dathe, K., Author
Nardone, A. M., Author
Ferrari, P., Author
Landi, A., Author
Wittler, L.2, Author              
Timmermann, B.3, Author              
Chan, D., Author
Mennen, U., Author
Klopocki, E.1, Author              
Mundlos, S.1, 4, 5, Author              
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1433557              
2Transgene Unit (Head: Lars Wittler), Scientific Service (Head: Manuela B. Urban), Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1479663              
3Sequencing, Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1433559              
4Institute for Medical Genetics and Human Genetics, Charité–Universitätsmedizin Berlin, Berlin, Germany, ou_persistent22              
5Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany, ou_persistent22              

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Free keywords: Animals Brachydactyly/ genetics Carpal Bones/abnormalities Comparative Genomic Hybridization/methods Elbow Joint/abnormalities Female Fingers/abnormalities Gene Deletion Gene Expression Regulation, Developmental Gene Rearrangement Genes, Homeobox Genetic Loci Genetic Predisposition to Disease Genome, Human Hand Deformities, Congenital/ genetics Humans Male Mice Mice, Transgenic Paired Box Transcription Factors/ genetics Sequence Analysis, DNA/methods Synostosis/ genetics Transformation, Genetic Translocation, Genetic Wrist Joint/abnormalities
 Abstract: The study of homeotic-transformation mutants in model organisms such as Drosophila revolutionized the field of developmental biology, but how these mutants relate to human developmental defects remains to be elucidated. Here, we show that Liebenberg syndrome, an autosomal-dominant upper-limb malformation, shows features of a homeotic limb transformation in which the arms have acquired morphological characteristics of a leg. Using high-resolution array comparative genomic hybridization and paired-end whole-genome sequencing, we identified two deletions and a translocation 5' of PITX1. The structural changes are likely to remove active PITX1 forelimb suppressor and/or insulator elements and thereby move active enhancer elements in the vicinity of the PITX1 regulatory landscape. We generated transgenic mice in which PITX1 was misexpressed under the control of a nearby enhancer and were able to recapitulate the Liebenberg phenotype.

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Language(s): eng - English
 Dates: 2012-09-272012-10
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.ajhg.2012.08.014
 Degree: -

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Title: American Journal of Human Genetics
Source Genre: Journal
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Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 91 (4) Sequence Number: - Start / End Page: 629 - 635 Identifier: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893