Section of Molecular Basis of Rare Disease, Genetics and Genomic Medicine Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
Eur J Endocrinol. 2021 May 25;185(1):121-135. doi: 10.1530/EJE-20-1453.
The transcription factor OTX2 is 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.
转录因子 OTX2 参与眼、颅面和垂体发育。
我们旨在确定 OTX2 突变在伴有/不伴眼部异常的先天性垂体功能减退症患者中的作用，研究其功能后果，并建立人类大脑中的 OTX2 表达，以研究其作用机制。
我们从英国（n=103）、国际中心（n=24）和巴西（n=282）筛选患者；145 例患者处于隔-视神经发育不良谱内，264 例患者无眼部表型。在鼠下丘脑 GT1-7 神经元中分析 OTX2 变体的转录激活能力。在人类胚胎脑切片上进行原位杂交。利用一系列 C 端 OTX2 变体生成基因工程小鼠。
在伴有眼部异常的个体中发现了两个染色体缺失和六个杂合不足突变；一名患者的一名受影响亲属携带相同的突变而无眼部表型。OTX2 截断导致显著的转录激活减少。在另一名无眼部异常的患者中发现了一个错义变体；然而，研究表明它很可能不是致病原因。在小鼠中，aa219 近端的截断导致无眼畸形，而远端的截断和错义变体则可耐受。在人类胚胎发生过程中，OTX2 在垂体后叶、视网膜、耳朵、丘脑、脉络丛中表达，部分在下丘脑表达，但不在垂体前叶表达。
OTX2 突变很少与孤立性无眼部异常的垂体功能减退症相关，即使在同一谱系中，也可能表现出不同的外显率。我们的数据表明，OTX2 突变患者的内分泌表型起源于下丘脑。
