J Clin Invest. 2013 Nov;123(11):4706-13. doi: 10.1172/JCI71400.
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 α (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.
神经性厌食症和神经性贪食症是常见且严重的饮食失调（ED），其病因不明。尽管遗传因素与 ED 的精神病理学有关，但尚未明确界定明确的生物学途径。收集了受 ED 影响的两个大家庭的 DNA，并通过全基因组测序（在连锁图谱之后）或全外显子组测序来鉴定与疾病共分离的突变。在第一个家庭中，对跨越三代的二十名成员进行分析，确定了雌激素相关受体α（ESRRA）基因中的罕见错义突变与疾病共分离。在第二个家庭中，对跨越四代的八名成员进行分析，确定了组蛋白去乙酰化酶 4（HDAC4）基因中的错义突变与疾病共分离。ESRRA 和 HDAC4 被确定在体外的 HeLa 细胞和体内的小鼠皮质中相互作用。转录分析显示，HDAC4 强烈抑制已知的 ESRRA 诱导靶基因的表达。对候选突变的生化分析表明，鉴定出的 ESRRA 突变降低了其转录活性，而 HDAC4 突变增加了 ESRRA 的转录抑制。我们的研究结果表明，导致 ESRRA 活性降低的突变会增加患 ED 的风险。
