The Pex1-G844D mouse: a model for mild human Zellweger spectrum disorder.
The Pex1-G844D mouse: a model for mild human Zellweger spectrum disorder.
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DOI：
10.1016/j.ymgme.2014.01.008
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发表时间：
2014-04
影响因子：
3.8
通讯作者：
Steinberg SJ
中科院分区：
文献类型：
--
作者：
Hiebler S;Masuda T;Hacia JG;Moser AB;Faust PL;Liu A;Chowdhury N;Huang N;Lauer A;Bennett J;Watkins PA;Zack DJ;Braverman NE;Raymond GV;Steinberg SJ
Zellweger谱系障碍（ZSD）是一种疾病的连续性，导致在PEX基因的遗传缺陷所必需的正常过氧化物酶体组装。这些常染色体隐性遗传疾病影响大脑发育，也会导致出生后的肝脏，肾上腺和肾脏功能障碍，以及视力和听力丧失。在大约30%的ZSD患者中观察到的亚型PEX 1-G843 D错义等位基因与较轻的临床和生化表型相关，一些纯合子个体存活至成年早期。尽管如此，携带PEX 1-G843 D等位基因的受影响儿童仍有智力障碍、发育不良和明显的感觉缺陷。为了增强我们测试改善人类PEX 1-G843 D功能的候选疗法的能力，我们创建了新型Pex 1-G844 D敲入小鼠模型，该模型代表了常见人类突变的小鼠等效物。我们发现，Pex 1-G844 D纯合子小鼠重现了轻度ZSD病例的许多经典特征，包括生长迟缓和脂肪肝伴胆汁淤积。此外，电生理学、组织学和基因表达研究提供的证据表明，这些动物发生了与人类患者相似的视网膜病变，并有视锥细胞死亡的证据。与从具有PEX 1-G843 D等位基因的ZSD患者获得的皮肤成纤维细胞类似，我们证明了Pex 1-G844 D等位基因纯合子的鼠细胞对分子伴侣样化合物有反应，其使过氧化物酶体β-氧化正常化。因此，Pex 1-G844 D小鼠提供了一个强大的模型系统，用于测试解决ZSD最常见遗传原因的候选疗法。此外，这种小鼠模型将加强对发病机制的研究。
Zellweger spectrum disorder (ZSD) is a disease continuum that results from inherited defects in PEX genes essential for normal peroxisome assembly. These autosomal recessive disorders impact brain development and also cause postnatal liver, adrenal, and kidney dysfunction, as well as loss of vision and hearing. The hypomorphic PEX1-G843D missense allele, observed in approximately 30% of ZSD patients, is associated with milder clinical and biochemical phenotypes, with some homozygous individuals surviving into early adulthood. Nonetheless, affected children with the PEX1-G843D allele have intellectual disability, failure to thrive, and significant sensory deficits. To enhance our ability to test candidate therapies that improve human PEX1-G843D function, we created the novel Pex1-G844D knock-in mouse model that represents the murine equivalent of the common human mutation. We show that Pex1-G844D homozygous mice recapitulate many classic features of mild ZSD cases, including growth retardation and fatty livers with cholestasis. In addition, electrophysiology, histology, and gene expression studies provide evidence that these animals develop a retinopathy similar to that observed in human patients, with evidence of cone photoreceptor cell death. Similar to skin fibroblasts obtained from ZSD patients with a PEX1-G843D allele, we demonstrate that murine cells homozygous for the Pex1-G844D allele respond to chaperone-like compounds, which normalizes peroxisomal β-oxidation. Thus, the Pex1-G844D mouse provides a powerful model system for testing candidate therapies that address the most common genetic cause of ZSD. In addition, this murine model will enhance studies focused on mechanisms of pathogenesis.