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

Malte Spielmann, Francesco Brancati, Peter M. Krawitz, Peter N. Robinson, Daniel M. Ibrahim, Martin Franke, Jochen Hecht, Silke Lohan, Katarina Dathe, Anna Maria Nardone, Paola Ferrari, Antonio Landi, Lars Wittler, Bernd Timmermann, Danny Chan, Ulrich Mennen, Eva Klopocki, Stefan Mundlos

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)629-635
Number of pages7
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - Oct 5 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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