权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular basis of Charcot-Marie-Tooth disease

腓骨肌萎缩症的分子基础

基本信息

批准号：
21591311
负责人：
HAYASAKA Kiyoshi
金额：
$ 2.91万
依托单位：
Yamagata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

项目摘要

To study the genetic background of Japanese Charcot-Marie-Tooth disease (CMT) patients, we analyzed qualitative and quantitative changes in the disease-causing genes mainly by denaturing high performance liquid chromatography and multiplex ligation-dependent probe analysis in 227 patients with demyelinating CMT and 127 patients with axonal CMT. In demyelinating CMT, we identified 53 patients with PMP22 duplication, 10 patients with PMP22 mutations, 20 patients with MPZ mutations, eight patients with NEFL mutations, 19 patients with GJB1 mutations, one patient with EGR2 mutation, five patients with PRX mutations and no mutations in 111 patients. In axonal CMT, we found 14 patients with MFN2 mutations, one patient with GARS mutation, five patients with MPZ mutations, one patient with GDAP1 mutation, six patients with GJB1 mutations and no mutations in 100 patients. Most of the patients carrying PMP22, MPZ, NEFL, PRX and MFN2 mutations showed early onset, whereas half of the patients carrying PMP22 duplication and all patients with GJB1 or MPZ mutations showing axonal phenotype were adult onset. Our data showed that a low prevalence of PMP22 duplication and high frequency of an unknown cause are features of Japanese CMT. Low prevalence of PMP22 duplication is likely associated with the mild symptoms due to genetic and/or epigenetic modifying factors.We found the OPA1 compound heterozygous mutations in the siblings who had optic atrophy, deafness and renal tubular acidosis and the IFN2 mutations in the patients complicated FSGS. We also the linkage in the family with recessive demyelinating CMT, but cannot still identify the causing geneIt will be necessary to establish a high-throughput method for screening of many disease-causing genes and to resequence the whole genome of patients with unidentified mutations to detect a new disease-causing gene.

为了研究日本腓骨肌萎缩症（CMT）患者的遗传背景，我们主要通过变性高效液相色谱和多重连接依赖探针分析对227例脱髓鞘CMT和127例轴突型CMT患者的致病基因进行了定性和定量分析。在脱髓鞘CMT中，我们确定了53例PMP22重复患者，10例PMP22突变患者，20例MPZ突变患者，8例NEFL突变患者，19例GJB1突变患者，1例EGR2突变患者，5例PRX突变患者，111例患者无突变。在100例轴突型CMT患者中，我们发现14例MFN2突变，1例加尔斯突变，5例MPZ突变，1例GDAP 1突变，6例GJB 1突变，无突变。大多数携带PMP22、MPZ、NEFL、PRX和MFN 2突变的患者表现为早发性，而一半携带PMP22重复的患者和所有携带GJB 1或MPZ突变的患者表现为轴突表型，均为成人发病。我们的数据表明，低患病率的PMP 22重复和高频率的一个未知的原因是日本CMT的特点。在伴有视神经萎缩、耳聋和肾小管性酸中毒的同胞中发现OPA 1复合杂合突变，在伴有FSGS的患者中发现IFN 2突变。我们也发现了隐性脱髓鞘CMT家系中的连锁，但仍不能确定致病基因，因此有必要建立一种高通量的方法来筛选许多致病基因，并对具有未知突变的患者的全基因组进行重测序以检测新的致病基因。