Molecular basis of Charcot-Marie-Tooth disease

为探讨日本夏科-玛丽-图思病(CMT)的遗传背景，我们对227例脱髓鞘CMT患者和127例轴索CMT患者的致病基因进行了定性和定量分析。在脱髓鞘CMT中，我们发现PMP22重复53例，PMP22突变10例，MPZ突变20例，NEFL突变8例，GJB1突变19例，EGR2突变1例，Prx突变5例，111例无突变。在轴突CMT中，发现Mfn2突变14例，GARS突变1例，MPZ突变5例，GDAP1突变1例，GJB1突变6例，100例中无突变。携带PMP22、MPZ、NEFL、Prx和Mfn2突变的患者大多发病早，而携带PMP22重复和GJB1或MPZ突变表现为轴突表型的患者中有一半为成人发病。我们的数据显示，PMP22重复的低发生率和原因不明的高频率是日本CMT的特征。PMP22重复的低发生率可能与遗传和/或表观遗传修饰因素导致的症状轻微有关。我们在有视神经萎缩、耳聋和肾小管酸中毒的同胞中发现了OPA1复合杂合突变，在合并FSGS的患者中发现了IFN2突变。我们也发现了隐性脱髓鞘CMT家族中的连锁，但仍不能确定致病基因。有必要建立一种高通量的方法来筛选许多致病基因，并对具有不明突变的患者的整个基因组进行重新测序，以检测新的致病基因。

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.