Disruption of autoregulatory feedback by a mutation in a remote, ultraconserved PAX6 enhancer causes aniridia.
Am J Hum Genet
; 93(6): 1126-34, 2013 Dec 05.
Article
em En
| MEDLINE
| ID: mdl-24290376
ABSTRACT
The strictly regulated expression of most pleiotropic developmental control genes is critically dependent on the activity of long-range cis-regulatory elements. This was revealed by the identification of individuals with a genetic condition lacking coding-region mutations in the gene commonly associated with the disease but having a variety of nearby chromosomal abnormalities, collectively described as cis-ruption disease cases. The congenital eye malformation aniridia is caused by haploinsufficiency of the developmental regulator PAX6. We discovered a de novo point mutation in an ultraconserved cis-element located 150 kb downstream from PAX6 in an affected individual with intact coding region and chromosomal locus. The element SIMO acts as a strong enhancer in developing ocular structures. The mutation disrupts an autoregulatory PAX6 binding site, causing loss of enhancer activity, resulting in defective maintenance of PAX6 expression. These findings reveal a distinct regulatory mechanism for genetic disease by disruption of an autoregulatory feedback loop critical for maintenance of gene expression through development.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
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Aniridia
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Elementos Facilitadores Genéticos
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Proteínas de Homeodomínio
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Fatores de Transcrição Box Pareados
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Proteínas do Olho
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Homeostase
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Mutação
Tipo de estudo:
Diagnostic_studies
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Etiology_studies
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Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article