Additive dominant effect of a SOX10 mutation underlies a complex phenotype of PCWH
Additive dominant effect of a SOX10 mutation underlies a complex phenotype of PCWH
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DOI：
10.1016/j.nbd.2015.04.013
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发表时间：
2015-08-01
影响因子：
6.1
通讯作者：
Inoue, Ken
中科院分区：
文献类型：
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作者：
Ito, Yukiko;Inoue, Naoko;Inoue, Ken
不同类型的SOX 10突变导致外周脱髓鞘性神经病、中枢性髓鞘形成障碍性脑白质营养不良、Waardenburg综合征和先天性巨结肠症，统称为PCWH。与此同时，由等位基因功能丧失突变引起的SOX 10单倍不足导致了一种较轻的非神经系统疾病，即Waardenburg-Hirschsprung病。体内更复杂的PCWH表型的细胞发病机制尚未完全了解。为了确定PCWH的发病机制，我们建立了转基因小鼠模型。通过细菌人工染色体（BAC）转基因，将已知的导致PCWH的SOX 10突变c.1400deI12引入小鼠Sox 10表达细胞。通过杂交多个转基因品系，我们检查了由不同拷贝数的突变转基因产生的效果。在神经系统内，转基因小鼠表现出延迟雪旺细胞在坐骨神经中的掺入和脊髓中少突胶质细胞的终末分化。转基因小鼠还表现出黑素细胞缺陷，表现为神经感觉性耳聋和异常皮肤色素沉着，以及肠神经系统的丧失。每个谱系的表型在携带更高拷贝数的小鼠中更严重，表明突变体SOX 10的基因剂量效应。通过在体内解除功能获得性和单倍不足的影响，我们已经证明了PCWH引起的SOX 10突变的影响在每个SOX 10表达细胞谱系中以剂量依赖性方式是唯一致病性的。在外周和中枢神经系统中，SOX 10突变的主要后果是髓鞘形成不足。PCWH患者复杂的神经系统表型可能是单倍不足和加性显性效应的组合所致。(C)2015 Elsevier Inc. All rights reserved.
Distinct classes of SOX10 mutations result in peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease, collectively known as PCWH. Meanwhile, SOX10 haploinsufficiency caused by allelic loss-of-function mutations leads to a milder non-neurological disorder, Waardenburg-Hirschsprung disease. The cellular pathogenesis of more complex PCWH phenotypes in vivo has not been thoroughly understood. To determine the pathogenesis of PCWH, we have established a transgenic mouse model. A known PCWH-causing SOX10 mutation, c.1400deI12, was introduced into mouse Sox10-expressing cells by means of bacterial artificial chromosome (BAC) transgenesis. By crossing the multiple transgenic lines, we examined the effects produced by various copy numbers of the mutant transgene. Within the nervous systems, transgenic mice revealed a delay in the incorporation of Schwann cells in the sciatic nerve and the terminal differentiation of oligodendrocytes in the spinal cord. Transgenic mice also showed defects in melanocytes presenting as neurosensory deafness and abnormal skin pigmentation, and a loss of the enteric nervous system. Phenotypes in each lineage were more severe in mice carrying higher copy numbers, suggesting a gene dosage effect for mutant SOX10. By uncoupling the effects of gain-of-function and haploinsufficiency in vivo, we have demonstrated that the effect of a PCWH-causing SOX10 mutation is solely pathogenic in each SOX10-expressing cellular lineage in a dosage-dependent manner. In both the peripheral and central nervous systems, the primary consequence of SOX10 mutations is hypomyelination. The complex neurological phenotypes in PCWH patients likely result from a combination of haploinsufficiency and additive dominant effect. (C) 2015 Elsevier Inc. All rights reserved.