ZNF764 Haploinsufficiency May Explain Partial Glucocorticoid, Androgen, and Thyroid Hormone Resistance Associated with 16p11.2 Microdeletion
ZNF764 Haploinsufficiency May Explain Partial Glucocorticoid, Androgen, and Thyroid Hormone Resistance Associated with 16p11.2 Microdeletion
复制标题
DOI：
10.1210/jc.2011-3493
复制
发表时间：
2012-08-01
影响因子：
5.8
通讯作者：
Stratakis, Constantine A.
中科院分区：
文献类型：
--
作者：
Kino, Tomoshige;Pavlatou, Maria G.;Stratakis, Constantine A.
内容：核激素受体通过共享的辅因子分子发挥其转录作用;因此，这些中间蛋白的缺陷可能与多种激素抗性相关。小染色体片段的微缺失导致遗传性或散发性疾病，通过影响居住genes.Objectives的表达：我们描述了一个7岁的男孩与糖皮质激素，甲状腺激素，并可能雄激素的部分抵抗。他被诊断为自闭症谱系障碍，并有发育迟缓和几个面部形态表现。我们探讨基因负责多种激素抵抗的情况下，结果：我们发现在这个病人的一个约1.1 Mb杂合16 p11.2微缺失，其中包括一个约500 kb的独特缺失沿着共同的，以前报道的约600 kb的16 p11.2微缺失。小干扰RNA为基础的筛选显示，ZNF 764，这是位于我们的情况下，独特的缺失片段的敲低，显着降低糖皮质激素，雄激素和甲状腺激素诱导的转录活性的响应基因在HeLa细胞，而其过表达增强其转录活性。这些细胞中雌激素和孕激素受体、cAMP反应元件结合蛋白和p53的活性不受影响。ZNF 764（锌指蛋白764）的表达在患者的外周血单核细胞减少，而外源性补充ZNF 764恢复患者的EB病毒转化淋巴细胞对糖皮质激素的反应。ZNF 764对糖皮质激素受体转录活性的影响是通过与一种通用的核激素受体辅激活因子--转录中介因子1协同作用而介导的。结论：ZNF 764微缺失导致的单倍不足可能是本例患者部分性多激素抵抗的原因。ZNF 764似乎参与糖皮质激素、雄激素和甲状腺激素的作用。（临床内分泌代谢杂志97：E1557-E1566，2012）
Context: Nuclear hormone receptors exert their transcriptional effects through shared cofactor molecules; thus, defects in such intermediate proteins may be associated with multiple hormone resistance. Microdeletion of small chromosomal segments results in hereditary or sporadic diseases by affecting expression of residing genes.Objectives: We describe a 7-yr-old boy with partial resistance to glucocorticoids, thyroid hormones, and possibly androgens. He was diagnosed as being in the autism spectrum disorder and had developmental delay and several facial morphological manifestations. We explored genes responsible for multiple hormone resistance of this case.Results: We found in this patient an approximately 1.1-Mb heterozygous 16p11.2 microdeletion, which included an approximately 500-kb unique deletion along with the common, previously reported approximately 600-kb 16p11.2 microdeletion. The small interfering RNA-based screening revealed that knockdown of ZNF764, which is located in the deleted segment unique to our case, significantly reduced glucocorticoid-, androgen-, and thyroid hormone-induced transcriptional activity of their responsive genes in HeLa cells, whereas its overexpression enhanced their transcriptional activity. The activities of the estrogen and progesterone receptors, cAMP response element-binding protein, and p53 were not affected in these cells. ZNF764 (zinc finger protein 764) expression was reduced in the patient's peripheral blood mononuclear cells, whereas exogenously supplemented ZNF764 recovered responsiveness to glucocorticoids in the patient's Epstein-Barr virus-transformed lymphocytes. The effect of ZNF764 on the glucocorticoid receptor transcriptional activity was mediated through cooperation with a general nuclear hormone receptor coactivator, transcriptional intermediary factor 1.Conclusions: ZNF764 haploinsufficiency caused by microdeletion may be responsible for the partial multiple hormone resistance observed in our patient. ZNF764 appears to be involved in glucocorticoid, androgen, and thyroid hormone action. (J Clin Endocrinol Metab 97: E1557-E1566, 2012)