Boerkoel Cornelius F, Takashima Hiroshi, Garcia Carlos A, Olney Richard K, Johnson John, Berry Katherine, Russo Paul, Kennedy Shelley, Teebi Ahmad S, Scavina Mena, Williams Lowell L, Mancias Pedro, Butler Ian J, Krajewski Karen, Shy Michael, Lupski James R
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Ann Neurol. 2002 Feb;51(2):190-201. doi: 10.1002/ana.10089.
Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disorder that has been associated with alterations of several proteins: peripheral myelin protein 22, myelin protein zero, connexin 32, early growth response factor 2, periaxin, myotubularin related protein 2, N-myc downstream regulated gene 1 product, neurofilament light chain, and kinesin 1B. To determine the frequency of mutations in these genes among patients with CMT or a related peripheral neuropathy, we identified 153 unrelated patients who enrolled prior to the availability of clinical testing, 79 had a 17p12 duplication (CMT1A duplication), 11 a connexin 32 mutation, 5 a myelin protein zero mutation, 5 a peripheral myelin protein 22 mutation, 1 an early growth response factor 2 mutation, 1 a periaxin mutation, 0 a myotubularin related protein 2 mutation, 1 a neurofilament light chain mutation, and 50 had no identifiable mutation; the N-myc downstream regulated gene 1 and the kinesin 1B gene were not screened for mutations. In the process of screening the above cohort of patients as well as other patients for CMT-causative mutations, we identified several previously unreported mutant alleles: two for connexin 32, three for myelin protein zero, and two for peripheral myelin protein 22. The peripheral myelin protein 22 mutation W28R was associated with CMT1 and profound deafness. One patient with a CMT2 clinical phenotype had three myelin protein zero mutations (I89N+V92M+I162M). Because one-third of the mutations we report arose de novo and thereby caused chronic sporadic neuropathy, we conclude that molecular diagnosis is a necessary adjunct for clinical diagnosis and management of inherited and sporadic neuropathy.
夏科 - 马里 - 图斯病（CMT）是一种具有遗传异质性的疾病，与多种蛋白质的改变有关：外周髓鞘蛋白22、髓鞘蛋白零、连接蛋白32、早期生长反应因子2、外周蛋白、与肌管素相关的蛋白2、N - myc下游调控基因1产物、神经丝轻链和驱动蛋白1B。为了确定这些基因在CMT患者或相关周围神经病变患者中的突变频率，我们确定了153例在临床检测可用之前入组的无亲缘关系患者，其中79例有17p12重复（CMT1A重复），11例有连接蛋白32突变，5例有髓鞘蛋白零突变，5例有外周髓鞘蛋白22突变，1例有早期生长反应因子2突变，1例有外周蛋白突变，0例有与肌管素相关的蛋白2突变，1例有神经丝轻链突变，50例未发现可识别的突变；未筛查N - myc下游调控基因1和驱动蛋白1B基因的突变。在对上述患者队列以及其他CMT致病突变患者进行筛查的过程中，我们发现了几个以前未报告的突变等位基因：连接蛋白32有两个，髓鞘蛋白零有三个，外周髓鞘蛋白22有两个。外周髓鞘蛋白22突变W28R与CMT1和严重耳聋有关。一名具有CMT2临床表型的患者有三个髓鞘蛋白零突变（I89N + V92M + I162M）。由于我们报告的突变中有三分之一是新发的，从而导致慢性散发性神经病变，我们得出结论，分子诊断是遗传性和散发性神经病变临床诊断和管理的必要辅助手段。
