期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 92, 期 1, 页码 114-125出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2012.11.008
关键词
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资金
- Juvenile Diabetes Research Foundation [17-2011-16, 2-2010-567, 26-2008-639]
- Institut National de la Sante et de la Recherche Medicale AVENIR program
- European Research Council [StG-2011-281265]
- National Health and Medical Research Council of Australia [1008077, 508043, 1002732]
- Foundation Telethon grant
- Fondation Jerome Lejeune grant
Intellectual disability (ID) and epilepsy often occur together and have a dramatic impact on the development and quality of life of the affected children. Polyalanine (polyA)-expansion-encoding mutations of aristaless-related homeobox (ARX) cause a spectrum of X-linked ID (XLID) diseases and chronic epilepsy, including infantile spasms. We show that lysine-specific demethylase 5C (KDM5C), a gene known to be mutated in XLID-affected children and involved in chromatin remodeling, is directly regulated by ARX through the binding in a conserved noncoding element. We have studied altered ARX carrying various polyA elongations in individuals with XLID and/or epilepsy. The changes in polyA repeats cause hypomorphic ARX alterations, which exhibit a decreased trans-activity and reduced, but not abolished, binding to the KDM5C regulatory region. The altered functioning of the mutants tested is likely to correlate with the severity of XLID and/or epilepsy. By quantitative RT-PCR, we observed a dramatic Kdm5c mRNA downregulation in murine Arx-knockout embryonic and neural stem cells. Such Kdm5c mRNA diminution led to a severe decrease in the KDM5C content during in vitro neuronal differentiation, which inversely correlated with an increase in H3K4me3 signal. We established that ARX polyA alterations damage the regulation of KDM5C expression, and we propose a potential ARX-dependent path acting via chromatin remodeling.
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