The rare Alus element-mediated chimerism of multiple de novo complex rearrangement sequences in GAN result in giant axonal neuropathy
The rare Alus element-mediated chimerism of multiple de novo complex rearrangement sequences in GAN result in giant axonal neuropathy
复制标题
GAN 中罕见的 Alus 元件介导的多个从头复杂重排序列的嵌合导致巨大轴突神经病。
DOI：
10.1016/j.cca.2019.12.017
复制
发表时间：
2020-03-01
影响因子：
5
通讯作者：
Wu, Lingqian
中科院分区：
文献类型：
--
作者：
Shi, Meizhen;Chen, Xin;Wu, Lingqian
巨轴索神经病（GAN）是一种罕见而严重的常染色体隐性遗传性神经退行性疾病，由于GAN功能缺失突变所致。然而，GAN的复杂重排序列的嵌合性至今未见报道，其复杂重排的机制仍有待确定。我们确定了一个具有GAN临床症状的家族，旨在揭示这种疾病的遗传原因。通过对患者进行全外显子组测序，我们在GAN中发现了一种新的纯合移码突变，缺失1 bp（c.27delC）。然而，当通过定量实时PCR和断裂点DNA测序分析患者的基因组DNA（gDNA）时，我们发现患者基因组中包含GAN外显子1的多个复杂重排序列的嵌合体。断裂点的微同源性和定位表明，它们可能是由Alu重复元件引起的。我们还发现患者淋巴细胞中GAN的mRNA表达水平降低，证实了这些突变的致病性。本研究首次报道了Alu元件介导的GAN中多种复杂重排序列镶嵌。这里的患者不是简单的纯合移码突变，而是复合杂合的父系c.27delC突变和GAN中多个从头复杂重排序列的嵌合体。我们的研究结果也可能为GAN中复杂重排的形成和致病性提供新的见解，并可能有助于遗传咨询和遗传检测。它还丰富了对正确的临床解释很重要的疾病相关数据库。
Giant axonal neuropathy (GAN) is a rare and grievous autosomal recessive neurodegenerative disease due to loss-of-function mutation in GAN. However, the chimerism of complex rearrangement sequences of GAN has not been reported so far, and the mechanism for its complex rearrangements remains to be determined. We identified a family with clinical symptoms of GAN and aimed to reveal a genetic cause underlying this disease. By whole-exome sequencing in the patient we identified a novel homozygous frameshift mutation with 1 bp deletion (c.27delC) in GAN. However, when analyzed the patient's genomic DNA (gDNA) by quantitative real-time PCR and breakpoint DNA sequencing, we found the chimerism of multiple complex rearrangement sequences encompassing exon 1 of GAN in the patient's genome. The microhomology and localization of the breakpoint indicated that they may be caused by Alu repeat elements. We also found that the mRNA expression level of GAN in patient's lymphocyte was decreased, confirming the pathogenicity of these mutations. Our study is the first reported on many complex rearrangement sequences mosaic in GAN mediated by Alu element. The patient here is not a simple homozygous frameshift mutation, but a compound heterozygous paternal c.27delC mutation and the chimerism of multiple de novo complex rearrangement sequences in GAN. Our results may also provide new insights into the formation and pathogenicity of complex rearrangement in GAN, and may be helpful to genetic counseling and genetic testing. It also enriches the Alu-mediated disease-associated database which are important for correct clinical interpretation.