Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.
Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
J Genet Genomics. 2022 Jul;49(7):654-665. doi: 10.1016/j.jgg.2021.11.011. Epub 2021 Dec 9.
Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1 (ELP1) gene that leads to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for FD headed to the discovery that homozygous deletion of the mouse Elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of ELP1, we generated two new mouse models by introducing different copy numbers of the human FD ELP1 transgene into the Elp1 knockout mouse (Elp1) and observed that human ELP1 expression rescues embryonic development in a dose-dependent manner. We then conducted a comprehensive transcriptome analysis in mouse embryos to identify genes and pathways whose expression correlates with the amount of ELP1. We found that ELP1 is essential for the expression of genes responsible for nervous system development. Further, gene length analysis of the differentially expressed genes showed that the loss of Elp1 mainly impacts the expression of long genes and that by gradually restoring Elongator, their expression is progressively rescued. Finally, through evaluation of co-expression modules, we identified gene sets with unique expression patterns that depended on ELP1 expression.
家族性自主神经异常（FD）是一种遗传性感觉和自主神经病变，由 Elongator 复合物蛋白 1（ELP1）基因突变引起，导致 ELP1 蛋白在组织中特异性减少。我们生成用于 FD 的表型小鼠模型的工作发现，Elp1 基因的纯合缺失导致胚胎在妊娠中期前死亡。鉴于 FD 是由 ELP1 的减少而不是缺失引起的，我们通过将人 FD ELP1 转基因的不同拷贝数引入 Elp1 敲除小鼠（Elp1）中生成了两种新的小鼠模型，并观察到人类 ELP1 的表达以剂量依赖的方式挽救了胚胎发育。然后，我们对小鼠胚胎进行了全面的转录组分析，以确定与 ELP1 表达量相关的基因和途径。我们发现 ELP1 对于负责神经系统发育的基因的表达是必需的。此外，差异表达基因的基因长度分析表明，Elp1 的缺失主要影响长基因的表达，并且通过逐渐恢复 Elongator，其表达逐渐得到挽救。最后，通过共表达模块的评估，我们确定了依赖于 ELP1 表达的具有独特表达模式的基因集。
