Myers Tracey D, Ferguson Carolyn, Gliniak Eric, Homanics Gregg E, Palladino Michael J
Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Curr Res Neurobiol. 2022 Nov 9;3:100062. doi: 10.1016/j.crneur.2022.100062. eCollection 2022.
Triosephosphate isomerase deficiency (TPI Df) is a rare, aggressive genetic disease that typically affects young children and currently has no established treatment. TPI Df is characterized by hemolytic anemia, progressive neuromuscular degeneration, and a markedly reduced lifespan. The disease has predominately been studied using invertebrate and models, which lack key aspects of the human disease. While other groups have generated mammalian mutant strains, specifically with the mouse these do not recapitulate key characteristic phenotypes of the human disease. Reported here is the generation of a novel murine model of TPI Df. CRISPR-Cas9 was utilized to engineer the most common human disease-causing mutation, and mice were also isolated as a frame-shifting deletion. mice experience a markedly shortened lifespan, postural abnormalities consistent with extensive neuromuscular dysfunction, hemolytic anemia, pathological changes in spleen, and decreased body weight. There is a ∼95% reduction in TPI protein levels in animals compared to wild-type littermates, consistent with decreased TPI protein stability, a known cause of TPI Df. This work illustrates the capability of mice to serve as a mammalian model of human TPI Df. This work will allow for advancement in the study of TPI Df within a model with physiology similar to humans. The development of the model reported here will enable mechanistic studies of disease pathogenesis and, importantly, efficacy testing in a mammalian system for emerging TPI Df treatments.
磷酸丙糖异构酶缺乏症（TPI Df）是一种罕见的、侵袭性的遗传性疾病，通常影响幼儿，目前尚无既定的治疗方法。TPI Df的特征是溶血性贫血、进行性神经肌肉变性和寿命明显缩短。该疾病主要使用缺乏人类疾病关键方面的无脊椎动物和模型进行研究。虽然其他研究小组已经培育出哺乳动物突变株，特别是小鼠，但这些突变株并未重现人类疾病的关键特征性表型。本文报道了一种新型的TPI Df小鼠模型的产生。利用CRISPR-Cas9技术构建了最常见的人类致病突变，同时也分离出了因移码缺失导致的小鼠。突变小鼠的寿命明显缩短，出现与广泛神经肌肉功能障碍一致的姿势异常、溶血性贫血、脾脏病理变化和体重减轻。与野生型同窝小鼠相比，突变动物体内的TPI蛋白水平降低了约95%，这与TPI蛋白稳定性降低一致，而TPI蛋白稳定性降低是TPI Df的一个已知病因。这项工作说明了突变小鼠可作为人类TPI Df的哺乳动物模型。这项工作将推动在生理上与人类相似的模型中对TPI Df的研究。本文报道的模型的开发将能够对疾病发病机制进行机制研究，重要的是，能够在哺乳动物系统中对新兴的TPI Df治疗方法进行疗效测试。
