Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
J Clin Invest. 2023 Jul 17;133(14):e160309. doi: 10.1172/JCI160309.
Mutations in HNRNPH2 cause an X-linked neurodevelopmental disorder with features that include developmental delay, motor function deficits, and seizures. More than 90% of patients with hnRNPH2 have a missense mutation within or adjacent to the nuclear localization signal (NLS) of hnRNPH2. Here, we report that hnRNPH2 NLS mutations caused reduced interaction with the nuclear transport receptor Kapβ2 and resulted in modest cytoplasmic accumulation of hnRNPH2. We generated 2 knockin mouse models with human-equivalent mutations in Hnrnph2 as well as Hnrnph2-KO mice. Knockin mice recapitulated clinical features of the human disorder, including reduced survival in male mice, impaired motor and cognitive functions, and increased susceptibility to audiogenic seizures. In contrast, 2 independent lines of Hnrnph2-KO mice showed no detectable phenotypes. Notably, KO mice had upregulated expression of Hnrnph1, a paralog of Hnrnph2, whereas knockin mice failed to upregulate Hnrnph1. Thus, genetic compensation by Hnrnph1 may counteract the loss of hnRNPH2. These findings suggest that HNRNPH2-related disorder may be driven by a toxic gain of function or a complex loss of HNRNPH2 function with impaired compensation by HNRNPH1. The knockin mice described here are an important resource for preclinical studies to assess the therapeutic benefit of gene replacement or knockdown of mutant hnRNPH2.
HNRNPH2 基因突变导致一种 X 连锁的神经发育障碍，其特征包括发育迟缓、运动功能缺陷和癫痫发作。超过 90%的 hnRNPH2 患者在 hnRNPH2 的核定位信号（NLS）内或附近存在错义突变。在这里，我们报告 hnRNPH2 NLS 突变导致与核转运受体 Kapβ2 的相互作用减少，并导致 hnRNPH2 适度的细胞质积累。我们生成了 2 个人源突变的 Hnrnph2 敲入小鼠模型以及 Hnrnph2-KO 小鼠。敲入小鼠重现了人类疾病的临床特征，包括雄性小鼠的存活率降低、运动和认知功能受损以及听觉性癫痫发作的易感性增加。相比之下，2 条独立的 Hnrnph2-KO 小鼠线没有表现出可检测的表型。值得注意的是，KO 小鼠中 Hnrnph1 的表达上调，Hnrnph1 是 Hnrnph2 的一个旁系同源物，而敲入小鼠未能上调 Hnrnph1。因此，Hnrnph1 的遗传补偿可能抵消了 hnRNPH2 的缺失。这些发现表明，HNRNPH2 相关疾病可能是由 hnRNPH2 功能的复杂丧失和 HNRNPH1 补偿受损导致的毒性获得功能驱动的。本文描述的敲入小鼠是进行临床前研究以评估突变型 hnRNPH2 基因替代或敲低治疗益处的重要资源。
