Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus.
Am J Hum Genet
; 91(4): 629-35, 2012 Oct 05.
Article
em En
| MEDLINE
| ID: mdl-23022097
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sinostose
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Transformação Genética
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Deformidades Congênitas da Mão
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Rearranjo Gênico
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Genes Homeobox
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Fatores de Transcrição Box Pareados
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Loci Gênicos
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Braquidactilia
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article