YIPF5 (p.W218R) mutation induced primary microcephaly in rabbits
YIPF5 (p.W218R) mutation induced primary microcephaly in rabbits
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DOI：
10.1016/j.nbd.2023.106135
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发表时间：
2023-05-13
影响因子：
6.1
通讯作者：
Song, Yuning
中科院分区：
文献类型：
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作者：
Liu, Xin;Yang, Jie;Song, Yuning
原发性小头畸形 (PMCPH) 是一种罕见的常染色体隐性神经发育障碍，全球 PMCPH 患病率为 0.0013% 至 0.15%。最近，YIPF5（p.W218R）中的纯合错义突变被确定为严重小头畸形的致病突变。在本研究中，我们利用 SpRY-ABEmax 介导的碱基替换构建了含有 YIPF5 (p.W218R) 突变的兔 PMCPH 模型，该模型精确地重现了人类 PMCPH 的典型症状。与野生型对照相比，突变兔表现出生长迟缓、头围减小、运动能力改变和存活率降低。基于模型兔的进一步研究阐明，皮质神经元中 YIPF5 功能的改变可能导致内质网应激和神经发育障碍，干扰顶祖细胞（AP）（发育中的皮质中的第一代祖细胞）的生成。此外，这些YIPF5突变兔支持内质网应激（ERS）诱导的未折叠蛋白反应（UPR）与PMCPH的发生之间的相关性，从而为YIPF5在人脑发育中的作用提供了新的视角，并为PMCPH的鉴别诊断和临床治疗提供了理论依据。据我们所知，这是第一个基因编辑的 PMCPH 兔子模型。该模型比传统的小鼠模型更好地模拟了人类小头畸形的临床特征。因此，它为理解 PMCPH 的发病机制和开发新的诊断和治疗方法提供了巨大的潜力。
Primary microcephaly (PMCPH) is a rare autosomal recessive neurodevelopmental disorder with a global prevalence of PMCPH ranging from 0.0013% to 0.15%. Recently, a homozygous missense mutation in YIPF5 (p. W218R) was identified as a causative mutation of severe microcephaly. In this study, we constructed a rabbit PMCPH model harboring YIPF5 (p.W218R) mutation using SpRY-ABEmax mediated base substitution, which precisely recapitulated the typical symptoms of human PMCPH. Compared with wild-type controls, the mutant rabbits exhibited stunted growth, reduced head circumference, altered motor ability, and decreased survival rates. Further investigation based on model rabbit elucidated that altered YIPF5 function in cortical neurons could lead to endoplasmic reticulum stress and neurodevelopmental disorders, interference of the generation of apical progenitors (APs), the first generation of progenitors in the developing cortex. Furthermore, these YIPF5- mutant rabbits support a correlation between unfolded protein responses (UPR) induced by endoplasmic retic-ulum stress (ERS), and the development of PMCPH, thus providing a new perspective on the role of YIPF5 in human brain development and a theoretical basis for the differential diagnosis and clinical treatment of PMCPH. To our knowledge, this is the first gene-edited rabbit model of PMCPH. The model better mimics the clinical features of human microcephaly than the traditional mouse models. Hence, it provides great potential for un-derstanding the pathogenesis and developing novel diagnostic and therapeutic approaches for PMCPH.