Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1
Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1
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DOI：
10.1038/s10038-019-0600-x
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发表时间：
2019-07-01
影响因子：
3.5
通讯作者：
Yamamoto, Toshiyuki
中科院分区：
文献类型：
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作者：
Yamamoto-Shimojima, Keiko;Imaizumi, Taichi;Yamamoto, Toshiyuki
Pelizaeus-Merzbacher 病 (PMD) 是一种由 PLP1 基因异常引起的 X 连锁隐性遗传病。大多数携带 PLP1 杂合异常的女性基本上没有症状。然而，由于X染色体失活的异常模式，一些女性携带者可能会出现症状。对一名未知痉挛性截瘫女性患者进行全外显子测序以获得分子诊断。结果，PLP1 中出现了从头杂合的单核苷酸缺失[NM_000533.5 (PLP1_v001)：c .783 del； p。 Thr262Leufs*20]被鉴定。在患者来源的类淋巴母细胞系中进行 RNA 测序，确认突变等位基因的单等位基因表达和野生型等位基因的异常失活。然后用 VX680 或 5azadC 处理患者来源的类淋巴母细胞系，从而恢复野生型等位基因的表达。因此，这两种药物有可能逆转 X 染色体的不适当倾斜失活。
Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder caused by abnormalities in the gene PLP1. Most females harboring heterozygous PLP1 abnormalities are basically asymptomatic. However, as a result of abnormal patterns of X-chromosome inactivation, it is possible for some female carriers to be symptomatic. Whole-exome sequencing of a female patient with unknown spastic paraplegia was performed to obtain a molecular diagnosis. As a result, a de novo heterozygous single-nucleotide deletion in PLP1 [NM_000533.5 (PLPl_v001): c .783 del; p. Thr262Leufs*20] was identified. RNA sequencing was performed in a patient-derived lymphoblastoid cell line, confirming mono-allelic expression of the mutated allele and abnormal inactivation of the wild-type allele. The patient-derived lymphoblastoid cell line was then treated with VX680 or 5azadC, which resulted in restored expression of the wild-type allele. These two agents thus have the potential to reverse inappropriately-skewed inactivation of the X-chromosome.