The phenotypic spectrum associated with OTX2 mutations in humans.
The phenotypic spectrum associated with OTX2 mutations in humans.
复制标题
与人类OTX2突变相关的表型频谱。
DOI：
10.1530/eje-20-1453
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发表时间：
2021-05-25
影响因子：
5.8
通讯作者：
Dattani MT
中科院分区：
文献类型：
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作者：
Gregory LC;Gergics P;Nakaguma M;Bando H;Patti G;McCabe MJ;Fang Q;Ma Q;Ozel AB;Li JZ;Poina MM;Jorge AAL;Benedetti AFF;Lerario AM;Arnhold IJP;Mendonca BB;Maghnie M;Camper SA;Carvalho LRS;Dattani MT
转录因子OTX2与眼、颅面和垂体发育有关。我们的目的是确定OTX2突变在有/无眼部异常的先天性垂体功能减退症患者中的作用，研究功能后果，并确定OTX2在人脑中的表达，以期研究作用机制。我们筛选了来自英国（n = 103）、国际中心（n = 24）和巴西（n = 282）的患者; 145例在视隔发育不良范围内，264例无眼表型。在鼠下丘脑GT1 - 7神经元中分析OTX2变体的反式激活能力。在人胚脑切片上进行原位杂交。用一系列C-末端OTX2变体产生基因工程小鼠。两个染色体缺失和六个单倍不足突变被确定在个人与眼睛异常;一个受影响的相对的一名患者窝藏相同的突变没有眼睛表型。OTX2截短导致显著的反式激活减少。在另一名无眼部异常的患者中发现了一种错义变体;然而，研究表明它很可能不是病因。在小鼠中，截短近端aa219引起无眼症，而远端截短和错义变体是耐受的。在人类胚胎发育过程中，OTX2在垂体后叶、视网膜、耳、丘脑、脉络丛和部分下丘脑中表达，但在垂体前叶中不表达。OTX2突变很少单独与垂体功能减退症相关，而不伴有眼部异常，并且即使在同一家系中，也可能是非特异性的。我们的数据表明，OTX2突变患者的内分泌表型是下丘脑起源的。
The transcription factor OTX2is implicated in ocular, craniofacial, and pituitary development. We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression in the human brain, with a view to investigate the mechanism of action. We screened patients from the UK (n = 103), international centres (n = 24), and Brazil (n = 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of OTX2 variants was analysed in murine hypothalamic GT1-7 neurons. In situ hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal OTX2 variants. Two chromosomal deletions and six haploinsufficient mutations were identified in individuals with eye abnormalities; an affected relative of one patient harboured the same mutation without an ocular phenotype. OTX2 truncations led to significant transactivation reduction. A missense variant was identified in another patient without eye abnormalities; however, studies revealed it was most likely not causative. In the mouse, truncations proximal to aa219 caused anophthalmia, while distal truncations and the missense variant were tolerated. During human embryogenesis, OTX2 was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary. OTX2 mutations are rarely associated with hypopituitarism in isolation without eye abnormalities, and may be variably penetrant, even within the same pedigree. Our data suggest that the endocrine phenotypes in patients with OTX2 mutations are of hypothalamic origin.