Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Medical Scientist Training Program, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Hum Mol Genet. 2020 May 8;29(7):1205-1217. doi: 10.1093/hmg/ddaa046.
The glycosylphosphatidylinositol (GPI) anchor is a post-translational modification added to approximately 150 different proteins to facilitate proper membrane anchoring and trafficking to lipid rafts. Biosynthesis and remodeling of the GPI anchor requires the activity of over 20 distinct genes. Defects in the biosynthesis of GPI anchors in humans lead to inherited glycosylphosphatidylinositol deficiency (IGD). IGD patients display a wide range of phenotypes though the central nervous system (CNS) appears to be the most commonly affected tissue. A full understanding of the etiology of these phenotypes has been hampered by the lack of animal models due to embryonic lethality of GPI biosynthesis gene null mutants. Here we model IGD by genetically ablating GPI production in the CNS with a conditional mouse allele of phosphatidylinositol glycan anchor biosynthesis, class A (Piga) and Nestin-Cre. We find that the mutants do not have structural brain defects but do not survive past weaning. The mutants show progressive decline with severe ataxia consistent with defects in cerebellar development. We show that the mutants have reduced myelination and defective Purkinje cell development. Surprisingly, we found that Piga was expressed in a fairly restricted pattern in the early postnatal brain consistent with the defects we observed in our model. Thus, we have generated a novel mouse model of the neurological defects of IGD which demonstrates a critical role for GPI biosynthesis in cerebellar and white matter development.
糖基磷脂酰肌醇（GPI）锚定是一种翻译后修饰，可添加到大约 150 种不同的蛋白质上，以促进适当的膜锚定和向脂筏的运输。GPI 锚定的生物合成和重塑需要 20 多种不同基因的活性。人类 GPI 锚定生物合成缺陷会导致遗传性糖基磷脂酰肌醇缺乏症（IGD）。尽管中枢神经系统（CNS）似乎是最常受影响的组织，但 IGD 患者表现出广泛的表型。由于 GPI 生物合成基因缺失突变体的胚胎致死性，缺乏动物模型一直阻碍着对这些表型病因的全面理解。在这里，我们通过使用条件性小鼠磷酸肌醇聚糖锚生物合成 A 类（Piga）和巢蛋白-Cre 基因敲除来遗传消除 CNS 中的 GPI 产生，从而模拟 IGD。我们发现突变体没有结构脑缺陷，但在断奶后不能存活。突变体表现出进行性下降，伴有严重的共济失调，与小脑发育缺陷一致。我们发现突变体的髓鞘形成减少，浦肯野细胞发育缺陷。令人惊讶的是，我们发现 Piga 在出生后早期的大脑中以相当受限的模式表达，与我们在模型中观察到的缺陷一致。因此，我们已经生成了一种新的 IGD 神经缺陷的小鼠模型，该模型证明了 GPI 生物合成在小脑和白质发育中的关键作用。
