Hubrecht Institute, Royal Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, The Netherlands.
PLoS One. 2009 Nov 19;4(11):e7910. doi: 10.1371/journal.pone.0007910.
Fragile X syndrome (FXS) is one of the most common known causes of inherited mental retardation. The gene mutated in FXS is named FMR1, and is well conserved from human to Drosophila. In order to generate a genetic tool to study FMR1 function during vertebrate development, we generated two mutant alleles of the fmr1 gene in zebrafish. Both alleles produce no detectable Fmr protein, and produce viable and fertile progeny with lack of obvious phenotypic features. This is in sharp contrast to published results based on morpholino mediated knock-down of fmr1, reporting defects in craniofacial development and neuronal branching in embryos. These phenotypes we specifically addressed in our knock-out animals, revealing no significant deviations from wild-type animals, suggesting that the published morpholino based fmr1 phenotypes are potential experimental artifacts. Therefore, their relation to fmr1 biology is questionable and morpholino induced fmr1 phenotypes should be avoided in screens for potential drugs suitable for the treatment of FXS. Importantly, a true genetic zebrafish model is now available which can be used to study FXS and to derive potential drugs for FXS treatment.
脆性 X 综合征 (FXS) 是最常见的遗传性智力障碍的已知原因之一。在 FXS 中发生突变的基因命名为 FMR1，从人类到果蝇都很好地保守。为了产生一种遗传工具来研究 FMR1 在脊椎动物发育过程中的功能，我们在斑马鱼中生成了两个突变的 fmr1 基因等位基因。这两个等位基因都不能产生可检测到的 Fmr 蛋白，但能产生存活且有生育能力的后代，没有明显的表型特征。这与基于 morpholino 介导的 fmr1 敲低的发表结果形成鲜明对比，该结果报告了胚胎中颅面发育和神经元分支的缺陷。我们在敲除动物中专门研究了这些表型，没有发现与野生型动物有显著差异，这表明发表的基于 morpholino 的 fmr1 表型可能是潜在的实验假象。因此，它们与 fmr1 生物学的关系值得怀疑，在筛选适合 FXS 治疗的潜在药物时，应避免使用 morpholino 诱导的 fmr1 表型。重要的是，现在有一个真正的遗传斑马鱼模型可用，可用于研究 FXS 并衍生潜在的 FXS 治疗药物。
