CHARCOT-MARIE-TOOTH DISEASE TYPE-1A - ASSOCIATION WITH A SPONTANEOUS POINT MUTATION IN THE PMP22 GENE
CHARCOT-MARIE-TOOTH DISEASE TYPE-1A - ASSOCIATION WITH A SPONTANEOUS POINT MUTATION IN THE PMP22 GENE
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DOI：
10.1056/nejm199307083290205
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发表时间：
1993-07-08
影响因子：
158.5
通讯作者：
LUPSKI, JR
中科院分区：
文献类型：
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作者：
ROA, BB;GARCIA, CA;LUPSKI, JR
背景腓骨肌萎缩症（CMT）是最常见的遗传性周围神经病。在大多数患者中，CMT 1A型与17号染色体p11.2-p12区域的1.5兆碱基（Mb）DNA重复相关。复制片段中基因剂量的增加似乎会导致这种疾病。编码髓磷脂蛋白的PMP 22基因已被定位在重复序列内，并被提出作为CMT 1A型的候选基因。我们分析了来自32名不相关的CMT 1型患者的DNA样本，这些患者在17p11.2-p12中没有1.5 Mb串联重复，以确定PMP 22编码区内的突变。分子生物学技术包括聚合酶链反应（PCR）、异源双链分析以检测点突变和PCR扩增产物的直接核苷酸序列测定。 一个10岁的男孩被鉴定出患有PMP 22的点突变，该点突变导致PMP 22的推定跨膜结构域中的丝氨酸被半胱氨酸取代。对家系成员的分析表明，PMP 22点突变是自发发生的，并与CMT 1型表型以常染色体显性模式分离。PMP 22点突变患者的临床和电生理表型与1.5Mb重复突变患者相似。 PMP 22基因在CMT 1型中具有致病作用。 PMP 22的点突变或包括PMP 22基因的区域的重复可导致疾病表型。
Background. Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. CMT type 1A is associated with a 1.5-megabase (Mb) DNA duplication in region p11.2-p12 of chromosome 17 in most patients. An increased dosage of a gene within the duplicated segment appears to cause the disease. The PMP22 gene, which encodes a myelin protein, has been mapped within the duplication and proposed as a candidate gene for CMT type 1A.Methods. We analyzed DNA samples from a cohort of 32 unrelated patients with CMT type 1 who did not have the 1.5-Mb tandem duplication in 17p11.2-p12 for mutations within the PMP22 coding region. Molecular techniques included the polymerase chain reaction (PCR), heteroduplex analysis to detect point mutations, and direct nucleotide-sequence determination of amplified PCR products.Results. A 10-year-old boy was identified with a point mutation in PMP22, which resulted in the substitution of cysteine for serine in a putative transmembrane domain of PMP22. Analysis of family members revealed that the PMP22 point mutation arose spontaneously and segregated with the CMT type 1 phenotype in an autosomal dominant pattern. The patients with the PMP22 point mutation had clinical and electrophysiologic phenotypes that were similar to those of patients with the 1.5-Mb duplication.Conclusions. The PMP22 gene has a causative role in CMT type 1. Either a point mutation in PMP22 or a duplication of the region including the PMP22 gene can result in the disease phenotype.