A Novel Dominant Negative Mutation of OTX2 Associated with Combined Pituitary Hormone Deficiency
A Novel Dominant Negative Mutation of OTX2 Associated with Combined Pituitary Hormone Deficiency
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DOI：
10.1210/jc.2008-1189
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发表时间：
2008-11-01
影响因子：
5.8
通讯作者：
Radovick, Sally
中科院分区：
文献类型：
--
作者：
Diaczok, Daniel;Romero, Christopher;Radovick, Sally
背景：合并垂体激素缺乏症（CPHD）的特点是缺乏一种以上的垂体前叶激素。在CPHD患者中发现了负责垂体细胞规格和基因表达的发育因子突变。OTX2是一种双歧类同源结构域蛋白，在前脑发育和HESX1启动子的转激活中都是必需的，但目前尚未发现与CPHD相关。目的：本研究的目的是鉴定和表征CPHD患者垂体特异性转录因子的新突变。设计：从垂体功能减退患者中分离基因组DNA，扩增并测序8种垂体特异性转录因子（HESX1、LHX3、LHX4、OTX2、PITX2、POU1F1、PROP1和SIX6）。新突变的特征是基于结构和功能研究。结果：我们描述了两名不相关的CPHD患儿，他们表现为新生儿低血糖，以及GH、TSH、LH、FSH和ACTH缺乏。磁共振显示垂体前叶发育不全伴垂体后叶异位。鉴定出一种新的OTX2杂合突变（N233S）。野生型和突变型OTX2蛋白与双体结合位点的结合相同，而突变型OTX2显示出降低的反活化。结论：一种新的OTX2突变与靶基因正常结合，并作为HESX1基因表达的显性阴性抑制剂。这表明HESX1是垂体前叶细胞类型时空发育所必需的，当HESX1的表达被破坏时，会导致垂体前叶缺失或发育不全，同时激素表达减少。这些结果证明了CPHD的一种新的机制，并扩展了我们对CPHD基因突变谱的认识。[J] .中华内分泌杂志，2003,19(3):559 - 559。
Context: Combined pituitary hormone deficiency (CPHD) is characterized by deficiencies in more than one anterior pituitary hormone. Mutations in developmental factors responsible for pituitary cell specification and gene expression have been found in CPHD patients. OTX2, a bicoid class homeodomain protein, is necessary for both forebrain development and transactivation of the HESX1 promoter, but as of yet, has not been associated with CPHD.Objective: The goal of this study was to identify and characterize novel mutations in pituitary specific transcription factors from CPHD patients.Design: Genomic DNA was isolated from patients with hypopituitarism to amplify and sequence eight pituitary specific transcription factors (HESX1, LHX3, LHX4, OTX2, PITX2, POU1F1, PROP1, and SIX6). Characterization of novel mutations is based on structural and functional studies.Results: We describe two unrelated children with CPHD who presented with neonatal hypoglycemia, and deficiencies of GH, TSH, LH, FSH, and ACTH. Magnetic resonance imaging revealed anterior pituitary hypoplasia with an ectopic posterior pituitary. A novel heterozygous OTX2 mutation (N233S) was identified. Wild-type and mutant OTX2 proteins bind equivalently to bicoid binding sites, whereas mutant OTX2 revealed decreased transactivation.Conclusions: A novel mutation in OTX2 binds normally to target genes and acts as a dominant negative inhibitor of HESX1 gene expression. This suggests that the expression of HESX1, required for spaciotemporal development of anterior pituitary cell types, when disrupted, results in an absent or underdeveloped anterior pituitary with diminished hormonal expression. These results demonstrate a novel mechanism for CPHD and extend our knowledge of the spectrum of gene mutations causing CPHD. (J Clin Endocrinol Metab 93: 4351-4359, 2008)