Molecular basis of Charcot-Marie-Tooth disease

为了研究日本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结扎依赖探针分析227例脱髓鞘性CMT患者和127例轴突性CMT患者的致病基因的定性和定量变化。在脱髓鞘CMT中，我们发现53例PMP22重复，10例PMP22突变，20例MPZ突变，8例NEFL突变，19例GJB1突变，1例EGR2突变，5例PRX突变，111例无突变。在轴突CMT中，我们发现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例患者无突变。携带PMP22、MPZ、NEFL、PRX和MFN2突变的患者大多为早期发病，而携带PMP22重复的患者和所有轴突表型的GJB1或MPZ突变的患者中有一半为成人发病。我们的数据显示，日本CMT的特点是PMP22重复率低，原因不明的发生率高。由于遗传和/或表观遗传修饰因素，PMP22复制的低患病率可能与轻度症状有关。我们在视神经萎缩、耳聋和肾小管酸中毒的兄弟姐妹中发现了OPA1复合杂合突变，在合并FSGS的患者中发现了IFN2突变。我们也发现了家族中与隐性脱髓鞘性CMT的连锁关系，但仍无法确定致病基因，因此有必要建立一种高通量的方法来筛选许多致病基因，并对突变不明的患者进行全基因组重测序以发现新的致病基因。

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.