hide
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.
