期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 93, 期 6, 页码 1126-1134出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2013.10.028
关键词
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资金
- National Institutes of Health [1RO1 EY01 8000-02]
- EU [Health-F4-2009-223262]
- Medical Research Council UK
- Medical Research Council [MC_U127527199, MC_PC_U127527199] Funding Source: researchfish
- MRC [MC_PC_U127527199, MC_U127527199] Funding Source: UKRI
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.
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