Eating disorder predisposition is associated with ESRRA and HDAC4 mutations
Eating disorder predisposition is associated with ESRRA and HDAC4 mutations
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DOI：
10.1172/jci71400
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发表时间：
2013-11-01
影响因子：
15.9
通讯作者：
Lutter, Michael
中科院分区：
文献类型：
--
作者：
Cui, Huxing;Moore, Jarrette;Lutter, Michael
神经性厌食症和神经性贪食症是常见的严重进食障碍，病因不明。虽然遗传因素已被牵连在精神病理学的ED，一个明确的生物途径尚未划定。从两个大家庭受ED影响的DNA收集，并与疾病分离的突变进行了鉴定，通过全基因组测序后的连锁图谱或全外显子组测序。在第一个家庭中，对三代20名成员的分析发现，雌激素相关受体a（ESRRA）基因中存在一种罕见的错义突变，这种突变与疾病分离。在第二个家族中，对四代八名成员的分析发现，组蛋白去乙酰化酶4（HDAC4）基因中存在一个错义突变，该突变与疾病分离。ESRRA和HDAC4被确定为在体外HeLa细胞中和体内小鼠皮质中相互作用。转录分析显示，HDAC4有效地抑制已知ESHRA诱导的靶基因的表达。候选突变的生化分析显示，所确定的ESRRA突变降低其转录活性，而HDAC4突变增加ESRRA的转录抑制。我们的研究结果表明，导致ESRRA活性降低的突变增加了发生ED的风险。
Anorexia nervosa and bulimia nervosa are common and severe eating disorders (EDs) of unknown etiology. Although genetic factors have been implicated in the psychopathology of EDs, a clear biological pathway has not been delineated. DNA from two large families affected by EDs was collected, and mutations segregating with illness were identified by whole-genome sequencing following linkage mapping or by whole-exome sequencing. In the first family, analysis of twenty members across three generations identified a rare missense mutation in the estrogen-related receptor a (ESRRA) gene that segregated with illness. In the second family, analysis of eight members across four generations identified a missense mutation in the histone deacetylase 4 (HDAC4) gene that segregated with illness. ESRRA and HDAC4 were determined to interact both in vitro in HeLa cells and in vivo in mouse cortex. Transcriptional analysis revealed that HDAC4 potently represses the expression of known ESRRA-induced target genes. Biochemical analysis of candidate mutations revealed that the identified ESRRA mutation decreased its transcriptional activity, while the HDAC4 mutation increased transcriptional repression of ESRRA. Our findings suggest that mutations that result in decreased ESRRA activity increase the risk of developing EDs.