Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes
Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes
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DOI：
10.1016/j.ajhg.2017.03.005
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发表时间：
2017-04-06
影响因子：
9.8
通讯作者：
Tesar, Paul J.
中科院分区：
文献类型：
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作者：
Nevin, Zachary S.;Factor, Daniel C.;Tesar, Paul J.
Pelizaeus-Merzbacher病（PMD）是中枢神经系统中的髓鞘的儿科疾病，并且表现出广泛的临床严重性。虽然PMD是一种罕见的单基因疾病，但已在人类中鉴定出X连锁髓鞘基因蛋白脂质蛋白1（PLP 1）的数百种突变。由于对PLP 1功能障碍的不完全理解和对原代人少突胶质细胞的有限获取，试图确定PMD的常见致病过程变得复杂。为了解决这个问题，我们从12个突变跨越PMD的遗传和临床多样性的个体中产生了人诱导多能干细胞（hiPSC）和hiPSC衍生的少突胶质细胞的面板，包括PLP 1的点突变和重复，三重和缺失，并开发了一个体外平台，用于同时对所有12个突变进行分子和细胞表征。我们确定了PLP 1 mRNA表达和剪接，少突胶质细胞祖细胞发育，少突胶质细胞形态和髓鞘形成能力的个体和共享缺陷。这些观察使PMD亚组的细胞内在表型分类，并确定了一个子集的突变内质网应激反应，改善形态和髓鞘形成缺陷的小分子调节剂的靶向测试。总的来说，这些数据提供了对各种PLP 1突变的发病机制的见解，并表明PMD的不同病因可能需要针对个体子集的特定治疗方法。更广泛地说，这项研究证明了基于hiPSC的小组跨越单一疾病内的突变异质性的多功能性，并建立了一个广泛适用的平台，用于任何人类髓鞘疾病的基因型-表型相关性和药物筛选。
Pelizaeus-Merzbacher disease (PMD) is a pediatric disease of myelin in the central nervous system and manifests with a wide spectrum of clinical severities. Although PMD is a rare monogenic disease, hundreds of mutations in the X-linked myelin gene proteolipid protein 1 (PLP1) have been identified in humans. Attempts to identify a common pathogenic process underlying PMD have been complicated by an incomplete understanding of PLP1 dysfunction and limited access to primary human oligodendrocytes. To address this, we generated panels of human induced pluripotent stem cells (hiPSCs) and hiPSC-derived oligodendrocytes from 12 individuals with mutations spanning the genetic and clinical diversity of PMD-including point mutations and duplication, triplication, and deletion of PLP1- and developed an in vitro platform for molecular and cellular characterization of all 12 mutations simultaneously. We identified individual and shared defects in PLP1 mRNA expression and splicing, oligodendrocyte progenitor development, and oligodendrocyte morphology and capacity for myelination. These observations enabled classification of PMD subgroups by cell-intrinsic phenotypes and identified a subset of mutations for targeted testing of small-molecule modulators of the endoplasmic reticulum stress response, which improved both morphologic and myelination defects. Collectively, these data provide insights into the pathogeneses of a variety of PLP1 mutations and suggest that disparate etiologies of PMD could require specific treatment approaches for subsets of individuals. More broadly, this study demonstrates the versatility of a hiPSC-based panel spanning the mutational heterogeneity within a single disease and establishes a widely applicable platform for genotype-phenotype correlation and drug screening in any human myelin disorder.