Mersiyanova I V, Perepelov A V, Polyakov A V, Sitnikov V F, Dadali E L, Oparin R B, Petrin A N, Evgrafov O V
Research Centre for Medical Genetics, Moscow, Russia.
Am J Hum Genet. 2000 Jul;67(1):37-46. doi: 10.1086/302962. Epub 2000 Jun 7.
Charcot-Marie-Tooth (CMT) disease is the most common inherited motor and sensory neuropathy. The axonal form of the disease is designated as "CMT type 2" (CMT2). Although four loci known to be implicated in autosomal dominant CMT2 have been mapped thus far (on 1p35-p36, 3q13. 1, 3q13-q22, and 7p14), no one causative gene is yet known. A large Russian family with CMT2 was found in the Mordovian Republic (Russia). Affected members had the typical CMT2 phenotype. Additionally, several patients suffered from hyperkeratosis, although the association, if any, between the two disorders is not clear. Linkage with the CMT loci already known (CMT1A, CMT1B, CMT2A, CMT2B, CMT2D, and a number of other CMT-related loci) was excluded. Genomewide screening pinpointed the disease locus in this family to chromosome 8p21, within a 16-cM interval between markers D8S136 and D8S1769. A maximum two-point LOD score of 5.93 was yielded by a microsatellite from the 5' region of the neurofilament-light gene (NF-L). Neurofilament proteins play an important role in axonal structure and are implicated in several neuronal disorders. Screening of affected family members for mutations in the NF-L gene and in the tightly linked neurofilament-medium gene (NF-M) revealed the only DNA alteration linked with the disease: a A998C transversion in the first exon of NF-L, which converts a conserved Gln333 amino acid to proline. This alteration was not found in 180 normal chromosomes. Twenty unrelated CMT2 patients, as well as 26 others with an undetermined form of CMT, also were screened for mutations in NF-L, but no additional mutations were found. It is suggested that Gln333Pro represents a rare disease-causing mutation, which results in the CMT2 phenotype.
夏科-马里-图思（CMT）病是最常见的遗传性运动和感觉神经病变。该病的轴索性形式被命名为“CMT2型”（CMT2）。尽管迄今为止已确定四个与常染色体显性CMT2相关的基因座（位于1p35 - p36、3q13.1、3q13 - q22和7p14），但尚未发现致病基因。在俄罗斯莫尔多瓦共和国发现了一个患有CMT2的俄罗斯大家庭。患病成员具有典型的CMT2表型。此外，几名患者患有角化过度，尽管这两种疾病之间的关联（如果有的话）尚不清楚。已排除与已知的CMT基因座（CMT1A、CMT1B、CMT2A、CMT2B、CMT2D以及其他一些与CMT相关的基因座）的连锁关系。全基因组筛查将该家族的疾病基因座定位到8号染色体的p21，位于标记D8S136和D8S1769之间16厘摩的区间内。来自神经丝轻链基因（NF-L）5'区域的一个微卫星产生了最高两点LOD分数5.93。神经丝蛋白在轴突结构中起重要作用，并与多种神经疾病有关。对患病家庭成员的NF-L基因和紧密连锁的神经丝中链基因（NF-M）进行突变筛查，发现了与该疾病相关的唯一DNA改变：NF-L第一个外显子中的A998C颠换，该突变将保守的谷氨酰胺333氨基酸转换为脯氨酸。在180条正常染色体中未发现这种改变。对20名无关的CMT2患者以及另外患有未确定形式CMT的26人也进行了NF-L突变筛查，但未发现其他突变。研究表明，谷氨酰胺333脯氨酸代表一种罕见的致病突变，它导致了CMT2表型。
