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

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Spielmann,  M.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Robinson,  P. N.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Franke,  M.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Hecht,  J.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Wittler,  L.
Transgene Unit (Head: Lars Wittler), Scientific Service (Head: Manuela B. Urban), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Timmermann,  B.
Sequencing, Max Planck Institute for Molecular Genetics, Max Planck Society;

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Klopocki,  E.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Mundlos,  S.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;
Institute for Medical Genetics and Human Genetics, Charité–Universitätsmedizin Berlin;
Berlin-Brandenburg Center for Regenerative Therapies;

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Citation

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.


Cite as: https://hdl.handle.net/11858/00-001M-0000-000E-F278-D
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.