Combined pituitary hormone deficiency (CPHD) is a genetically heterogeneous disorder caused by mutations in over 30 genes. The loss-of-function mutations in many of these genes, including orthodenticle homeobox 2 (OTX2), can present with a broad range of clinical symptoms, which provides a challenge for predicting phenotype from genotype. Another challenge in human genetics is functional evaluation of rare genetic variants that are predicted to be deleterious. Zebrafish are an excellent vertebrate model for evaluating gene function and disease pathogenesis, especially because large numbers of progeny can be obtained, overcoming the challenge of individual variation. To clarify the utility of zebrafish for the analysis of CPHD-related genes, we analyzed the effect of OTX2 loss of function in zebrafish. The otx2b gene is expressed in the developing hypothalamus, and otx2b^{hu3625/hu3625} fish exhibit multiple defects in the development of head structures and are not viable past 10 days post fertilization (dpf). Otx2b^{hu3625/hu3625} fish have a small hypothalamus and low expression of pituitary growth hormone and prolactin (prl). The gills of otx2b^{hu3625/hu3625} fish have weak sodium influx, consistent with the role of prolactin in osmoregulation. The otx2b^{hu3625/hu3625} eyes are microphthalmic with colobomas, which may underlie the inability of the mutant fish to find food. The small pituitary and eyes are associated with reduced cell proliferation and increased apoptosis evident at 3 and 5 dpf, respectively. These observations establish the zebrafish as a useful tool for the analysis of CPHD genes with variable and complex phenotypes.

中文翻译：

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Otx2b 突变斑马鱼具有可模拟哺乳动物疾病的垂体、眼睛和下颌骨缺陷。

联合垂体激素缺乏症 (CPHD) 是一种由 30 多个基因突变引起的遗传异质性疾病。许多这些基因的功能丧失突变，包括正牙同源框 2 (OTX2)，可以呈现广泛的临床症状，这为从基因型预测表型提供了挑战。人类遗传学的另一个挑战是对预测为有害的罕见遗传变异的功能评估。斑马鱼是评估基因功能和疾病发病机制的优秀脊椎动物模型，特别是因为可以获得大量后代，克服了个体变异的挑战。为了阐明斑马鱼在 CPHD 相关基因分析中的效用，我们分析了 OTX2 功能丧失对斑马鱼的影响。该otx2b基因在发育中的下丘脑中表达，otx2b ^{hu3625/hu3625}鱼在头部结构发育中表现出多种缺陷，并且在受精后 (dpf) 10 天后无法存活。Otx2b ^{hu3625/hu3625}鱼的下丘脑较小，垂体生长激素和催乳素 ( prl ) 的表达较低。otx2b ^{hu3625/hu3625}鱼的鳃有微弱的钠流入，与催乳素在渗透调节中的作用一致。该otx2b ^{hu3625 / hu3625}眼睛是带有缺损的小眼，这可能是突变鱼无法找到食物的原因。分别在 3 和 5 dpf 时，小垂体和眼睛与细胞增殖减少和细胞凋亡增加有关。这些观察结果使斑马鱼成为分析具有可变和复杂表型的 CPHD 基因的有用工具。