Department of Molecular and Cell and Developmental Biology, Institute for Cellular and Molecular Biology, Patterson 522, University of Texas at Austin, Austin, TX 78713, USA.
Dis Model Mech. 2013 Sep;6(5):1285-91. doi: 10.1242/dmm.011965. Epub 2013 May 29.
The severity of most human birth defects is highly variable. Our ability to diagnose, treat and prevent defects relies on our understanding of this variability. Mutation of the transcription factor GATA3 in humans causes the highly variable hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome. Although named for a triad of defects, individuals with HDR can also exhibit craniofacial defects. Through a forward genetic screen for craniofacial mutants, we isolated a zebrafish mutant in which the first cysteine of the second zinc finger of Gata3 is mutated. Because mutation of the homologous cysteine causes HDR in humans, these zebrafish mutants could be a quick and effective animal model for understanding the role of gata3 in the HDR disease spectrum. We demonstrate that, unexpectedly, the chaperone proteins Ahsa1 and Hsp90 promote severe craniofacial phenotypes in our zebrafish model of HDR syndrome. The strengths of the zebrafish system, including rapid development, genetic tractability and live imaging, make this an important model for variability.
大多数人类出生缺陷的严重程度具有高度可变性。我们对这种可变性的理解，是我们能够进行诊断、治疗和预防缺陷的基础。人类转录因子 GATA3 的突变会导致高度可变的甲状旁腺功能减退症、感觉神经性耳聋和肾脏发育不良（HDR）综合征。尽管该综合征以三联征命名，但 HDR 患者也可能表现出头面部缺陷。通过对颅面突变体进行正向遗传筛选，我们分离到一个 Gata3 第二个锌指的第二个半胱氨酸发生突变的斑马鱼突变体。由于同源半胱氨酸的突变会导致人类 HDR，因此这些斑马鱼突变体可能是一种快速有效的动物模型，有助于理解 gata3 在 HDR 疾病谱中的作用。我们发现，出乎意料的是，伴侣蛋白 Ahsa1 和 Hsp90 在我们的 HDR 综合征斑马鱼模型中促进严重的颅面表型。斑马鱼系统的优势，包括快速发育、遗传可操作性和活体成像，使其成为研究变异性的重要模型。
