Molecular Basis of Charcot-Marie-Tooth Disease

腓骨肌萎缩症的分子基础

• 批准号: 14570718
• 负责人: HAYASAKA Kiyoshi
• 金额: $ 2.24万
• 依托单位: Yamagata University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570718/
• 关键词: Hereditary neurophaties; Charcot-Marie-Tooth; sodium channel; denaturing high performance liquid chromatography; Nav 1.6; 17p11.2遺伝子重複; PMP22; Po; Cx32; EGR2SCN8A

Charcot-Marie-Tooth disease (CMT) is a most common hereditary neuropathy. CMT type 1 (CMT1), the major form of the disease, is a genetically heterogeneous disease and many responsible genes have been identified. However, disease-causing mutations have not been identified in many Japanese patients. We tried to establish the reliable and easy diagnostic method to make clear the molecular basis of Japanese patients. We also studied physiological properties of Nav 1.6 channel, which plays a significant role for signal transduction in the peripheral nervous system.We studied 143 patients with CMT1 and initially identified the CMT1A duplication in 40 patients. As for the patients without the CMT1A duplication, we screened the mutations of PMP22, Po, Cx32, EGR2, LITAF, GDAP1, MTMR2 and PRX using denaturing gradient gel electrophoresis (DGGE) and denaturing high performance liquid chromatography (DHPLC). We identified 7 patients with PMP22 mutations, 16 patients with Po mutations, 13 patients with Cx32 mutations, 1 patient with EGR2 mutation, 1 patient with MTMR2 and 3 patients with PRX mutations. Compared with the data from foreign countries, the patients due to CMT1A duplication were few and many patients (44%) were not identified their etiologies. Further study is needed to clarify the molecular basis of Japanese patients.We previously isolated cDNA of Nav 1.6 channel and examined biophysical properties of Nav 1.6 in heterologous expression cell systems using patch clamp method. We observed large persistent current of Nav 1.6 Channel in tsA201 cells however, the persistent current was significantly reduced by the co-expression with ankyrin G. It suggested that modulation by ankyrin G may underlie site-dependant electrophysiological Characteristics of Nav 106 channels.

Charcot-Marie-Tooth病(CMT)是最常见的遗传性神经病。CMT-1(CMT1)是该病的主要类型，是一种遗传异质性疾病，已发现许多致病基因。然而，在许多日本患者中还没有发现致病突变。我们试图建立一种可靠、简便的诊断方法，以明确日本患者的分子基础。我们还研究了NAV 1.6通道的生理特性，该通道在周围神经系统的信号转导中起着重要作用。我们研究了143例CMT1患者，初步确定了40例CMT1A重复。对于无CMT1A重复的患者，我们采用变性梯度凝胶电泳法(DGGE)和变性高效液相色谱(DHPLC)对PMP22、Po、Cx32、EGR2、LITAF、GDAP1、MTMR2和Prx突变进行了筛查。PMP22突变7例，Po突变16例，Cx32突变13例，EGR2突变1例，MTMR2突变1例，Prx突变3例。与国外资料相比，由于CMT1A重复引起的患者很少，许多患者(44%)的病因不明。日本患者的分子基础还需要进一步的研究。我们先前分离了NAV 1.6通道的cDNA，并在异源表达细胞系统中用膜片钳方法检测了NAV 1.6的生物物理特性。我们在tsA201细胞中观察到NAV 1.6通道的持续电流很大，但与锚蛋白G的共表达显著降低了通道的持续电流。提示锚蛋白G的调制可能是NAV 106通道位置依赖的电生理特性的基础。

项目成果

Chikahiko N. et al.: "Molecular Analysis in Japanese Patients With Charcot-Marie-Tooth Disease : DGGE Analysis for PMP22, MPZ, and Cx32/GJB1 Mutations"Human Mutation. 20. 392-398 (2002)

Chikahiko N. 等人：“日本腓骨肌萎缩症患者的分子分析：PMP22、MPZ 和 Cx32/GJB1 突变的 DGGE 分析”人类突变。

Numakura C et al.: "Molecular analysis in Japanese patients with Charcot-Marie-Tooth disease : DGGE analysis for PMP22, MPZ, and Cx32/GJB1 mutations"Hum Mutat.. 20. 392-398 (2002)

Numakura C 等人：“日本腓骨肌萎缩症患者的分子分析：PMP22、MPZ 和 Cx32/GJB1 突变的 DGGE 分析”Hum Mutat.. 20. 392-398 (2002)

SHiihara T et al.: "Progressive sliding hiatal hernia as a complication of Menkes' syndrome."J.Child Neurol.. 17. 401-402 (2002)

Shiihara T 等人：“进行性滑动性食管裂孔疝是门克斯综合征的并发症。”J.Child Neurol.. 17. 401-402 (2002)

Numakura C et al.: "Screening of the early growth response 2 gene in Japanese patients with Charcot-Marie-Tooth disease type 1."J Neurol Sci. 210. 61-64 (2003)

Numakura C 等人：“日本 1 型腓骨肌萎缩症患者早期生长反应 2 基因的筛选”，J Neurol Sci。

Kurihara S et al.: "Charcot-Marie-Tooth families in Japan with MPZ Thr124Met mutation"J Neurol Neurosurg Psych. in press.

Kurihara S 等人：“日本的 Charcot-Marie-Tooth 家族存在 MPZ Thr124Met 突变”J Neurol Neurosurg Psych。