Murine model of triosephosphate isomerase deficiency with anemia and severe neuromuscular dysfunction.
Murine model of triosephosphate isomerase deficiency with anemia and severe neuromuscular dysfunction.
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DOI：
10.1016/j.crneur.2022.100062
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Palladino, Michael J
中科院分区：
文献类型：
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作者：
Myers, Tracey D;Ferguson, Carolyn;Gliniak, Eric;Homanics, Gregg E;Palladino, Michael J
磷酸丙糖异构酶缺乏症 (TPIDf) 是一种罕见的侵袭性遗传病，通常影响幼儿，目前尚无成熟的治疗方法。 TPI Df 的特点是溶血性贫血、进行性神经肌肉变性和寿命显着缩短。该疾病主要使用无脊椎动物和体外模型进行研究，这些模型缺乏人类疾病的关键方面。虽然其他研究小组已经产生了哺乳动物 Tpi1 突变株，特别是小鼠小小鼠，但这些突变株并不能概括人类疾病的关键特征表型。这里报道的是一种新型 TPI Df 小鼠模型的产生。 CRISPR-Cas9被用来设计最常见的人类致病突变Tpi1E105D，并且Tpi1null小鼠也作为移码缺失被分离出来。 Tpi1E105D/缺失小鼠的寿命明显缩短，姿势异常，伴有广泛的神经肌肉功能障碍、溶血性贫血、脾脏病理变化和体重下降。与野生型同窝动物相比，Tpi1E105D/缺失动物的 TPI 蛋白水平降低了约 95%，这与 TPI 蛋白稳定性降低（TPI Df 的已知原因）一致。这项工作说明了 Tpi1E105D/null 小鼠作为人类 TPI Df 哺乳动物模型的能力。这项工作将有助于在与人类生理学相似的模型中推进 TPI Df 的研究。本文报道的模型的开发将使疾病发病机制的机制研究成为可能，更重要的是，能够在哺乳动物系统中测试新兴 TPI Df 治疗的功效。在这里，我们报告了 CRISPR 生成的 TPI Df 小鼠模型。该模型表现出寿命缩短、贫血和严重的神经行为缺陷。这是第一个具有神经肌肉表型的 TPI Df 小鼠模型。该模型将使新兴疗法的机制研究和功效测试成为可能。
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 in vitro models, which lack key aspects of the human disease. While other groups have generated mammalian Tpi1 mutant strains, specifically with the mouse mus musculus, 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, Tpi1E105D, and Tpi1null mice were also isolated as a frame-shifting deletion. Tpi1E105D/null 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 Tpi1E105D/null animals compared to wild-type littermates, consistent with decreased TPI protein stability, a known cause of TPI Df. This work illustrates the capability of Tpi1E105D/null 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. Here we report a CRISPR generated mouse model of TPI Df. The model exhibits reduced longevity, anemia, and severe neurobehavioral deficits. This is the first mouse model of TPI Df with neuromuscular phenotypes. This model will enable mechanistic studies and efficacy testing of emerging therapies.