Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
PLoS One. 2011;6(12):e29393. doi: 10.1371/journal.pone.0029393. Epub 2011 Dec 19.
Charcot-Marie-Tooth disease type 2 (CMT2) is a clinically and genetically heterogeneous group of inherited axonal neuropathies. The aim of this study was to extensively investigate the mutational spectrum of CMT2 in a cohort of patients of Han Chinese.
Genomic DNA from 36 unrelated Taiwanese CMT2 patients of Han Chinese descent was screened for mutations in the coding regions of the MFN2, RAB7, TRPV4, GARS, NEFL, HSPB1, MPZ, GDAP1, HSPB8, DNM2, AARS and YARS genes. Ten disparate mutations were identified in 14 patients (38.9% of the cohort), including p.N71Y in AARS (2.8%), p.T164A in HSPB1 (2.8%), and p.[H256R]+[R282H] in GDAP1 (2.8%) in one patient each, three NEFL mutations in six patients (16.7%) and four MFN2 mutations in five patients (13.9%). The following six mutations were novel: the individual AARS, HSPB1 and GDAP1 mutations and c.475-1G>T, p.L233V and p.E744M mutations in MFN2. An in vitro splicing assay revealed that the MFN2 c.475-1G>T mutation causes a 4 amino acid deletion (p.T159_Q162del). Despite an extensive survey, the genetic causes of CMT2 remained elusive in the remaining 22 CMT2 patients (61.1%).
This study illustrates the spectrum of CMT2 mutations in a Taiwanese CMT2 cohort and expands the number of CMT2-associated mutations. The relevance of the AARS and HSPB1 mutations in the pathogenesis of CMT2 is further highlighted. Moreover, the frequency of the NEFL mutations in this study cohort was unexpectedly high. Genetic testing for NEFL and MFN2 mutations should, therefore, be the first step in the molecular diagnosis of CMT2 in ethnic Chinese.
Charcot-Marie-Tooth 病 2 型（CMT2）是一组具有临床和遗传异质性的遗传性轴索性神经病。本研究的目的是广泛研究汉族人群中 CMT2 患者的突变谱。
从 36 名无亲缘关系的台湾汉族 CMT2 患者的基因组 DNA 中筛选出 MFN2、RAB7、TRPV4、GARS、NEFL、HSPB1、MPZ、GDAP1、HSPB8、DNM2、AARS 和 YARS 基因编码区的突变。在 14 名患者（队列的 38.9%）中发现了 10 种不同的突变，包括 AARS 中的 p.N71Y（2.8%）、HSPB1 中的 p.T164A（2.8%）和 GDAP1 中的 p.[H256R]+[R282H]（2.8%）各 1 例，6 名患者的 3 种 NEFL 突变（16.7%）和 5 名患者的 4 种 MFN2 突变（13.9%）。以下 6 种突变为新发现：个体 AARS、HSPB1 和 GDAP1 突变以及 MFN2 中的 c.475-1G>T、p.L233V 和 p.E744M 突变。体外剪接试验表明，MFN2 的 c.475-1G>T 突变导致 4 个氨基酸缺失（p.T159_Q162del）。尽管进行了广泛的调查，但在其余 22 名 CMT2 患者（61.1%）中，CMT2 的遗传原因仍未查明。
本研究说明了台湾 CMT2 队列中 CMT2 突变的谱，并扩展了 CMT2 相关突变的数量。AARS 和 HSPB1 突变在 CMT2 发病机制中的相关性进一步得到强调。此外，本研究队列中 NEFL 突变的频率出乎意料地高。因此，在中国人群中，CMT2 的分子诊断应首先进行 NEFL 和 MFN2 突变的基因检测。
