Hypomyelination, a neurological condition characterized by decreased production of myelin sheets by glial cells, often has no known etiology. Elucidating the genetic causes of hypomyelination provides a better understanding of myelination, as well as means to diagnose, council, and treat patients. Here, we present evidence that YIPPEE LIKE 3 (YPEL3), a gene whose developmental role was previously unknown, is required for central and peripheral glial cell development. We identified a child with a constellation of clinical features including cerebral hypomyelination, abnormal peripheral nerve conduction, hypotonia, areflexia, and hypertrophic peripheral nerves. Exome and genome sequencing revealed a de novo mutation that creates a frameshift in the open reading frame of YPEL3, leading to an early stop codon. We used zebrafish as a model system to validate that YPEL3 mutations are causative of neuropathy. We found that ypel3 is expressed in the zebrafish central and peripheral nervous system. Using CRISPR/Cas9 technology, we created zebrafish mutants carrying a genomic lesion similar to that of the patient. Our analysis revealed that Ypel3 is required for development of oligodendrocyte precursor cells, timely exit of the perineurial glial precursors from the central nervous system (CNS), formation of the perineurium, and Schwann cell maturation. Consistent with these observations, zebrafish ypel3 mutants have metabolomic signatures characteristic of oligodendrocyte and Schwann cell differentiation defects, show decreased levels of Myelin basic protein in the central and peripheral nervous system, and develop defasciculated peripheral nerves. Locomotion defects were observed in adult zebrafish ypel3 mutants. These studies demonstrate that Ypel3 is a novel gene required for perineurial cell development and glial myelination.

髓鞘形成不足是一种神经系统疾病，其特征是神经胶质细胞髓磷脂片的产生减少，通常没有已知的病因。阐明髓鞘形成不足的遗传原因可以更好地了解髓鞘形成，并提供诊断、咨询和治疗患者的方法。在这里，我们提出证据表明YIPPEE LIKE 3 (YPEL3)是中央和外周胶质细胞发育所必需的基因，其发育作用以前未知。我们发现一名儿童具有一系列临床特征，包括脑髓鞘形成不足、周围神经传导异常、张力减退、反射消失和周围神经肥大。外显子组和基因组测序揭示了一种从头突变，该突变在YPEL3的开放阅读框中产生移码，导致早期终止密码子。我们使用斑马鱼作为模型系统来验证YPEL3突变是神经病变的原因。我们发现ypel3在斑马鱼中枢和周围神经系统中表达。使用 CRISPR/Cas9 技术，我们创建了携带与患者相似的基因组病变的斑马鱼突变体。我们的分析表明，Ypel3 是少突胶质细胞前体细胞发育、神经束膜胶质前体细胞及时从中枢神经系统 (CNS) 退出、神经束膜形成和施万细胞成熟所必需的。与这些观察结果一致，斑马鱼ypel3突变体具有少突胶质细胞和雪旺细胞分化缺陷的代谢组学特征，显示中枢和周围神经系统中髓磷脂碱性蛋白水平降低，并发育出去束化的周围神经。 在成年斑马鱼ypel3突变体中观察到运动缺陷。这些研究表明，Ypel3 是神经束膜细胞发育和神经胶质髓鞘形成所需的新基因。