Connexin 32 Mutations in X-Linked CMT

X 连锁 CMT 中的连接蛋白 32 突变

• 批准号: 7569416
• 负责人: CHARLES K ABRAMS
• 金额: $ 14.93万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569416
• 关键词: Animal Model; Appearance; Basic Science; Biopsy; Calcium; Calcium Signaling; Cell membrane; Cells; Charcot-Marie-Tooth Disease; Chemicals; Clinical; Collaborations; Communication; Connexins; Coupled; Cyclic AMP; Cyclic Nucleotides; Development; Disease; Dyes; Environment; Epidemiology; Exercise; Fatigue; Gap Junctions; Genes; Grant; In Vitro; Independent Scientist Award; Inherited; Investigation; Ion Channel; Knock-in Mouse; Lead; Link; Liposomes; Measures; Mediating; Medicine; Membrane; Muscle Cramp; Mutation; Natural regeneration; Nature; Neuromuscular Diseases; Neurosciences; Pathology; Pathway interactions; Patients; Peripheral Nervous System Diseases; Permeability; Phenotype; Physicians; Predisposition; Property; Proteins; Research; Schwann Cells; Scientist; Second Messenger Systems; Severities; Signaling Molecule; Stimulus; Suicide; System; Techniques; Testing; Time; Translational Research; Work; Xenopus oocyte; college; connexin 32; cyclic-nucleotide gated ion channels; gene replacement; mutant; myelination; programs; reconstitution; research study; response; second messenger; voltage

X-linked Charcot Marie-Tooth Disease (CMTX) is an inherited peripheral neuropathy associated with mutations in the gap junction protein connexins 32 (Cx32). The central tenet of this proposal is that alterations in the functional properties of the ion channel formed by Cx32 can cause CMTX. Further, we propose that to understand the link between mutations and the disorder, we must explore the specific nature of the induced deficits in channel gating, permeability and control of formation. Although an association between a specific mutation in an ion channel and a neuromuscular disease is often compelling, the mechanism that underlies the deficit can remain unrevealed by clinical measures, morphologic examination or epidemiology. The studies )roposed in this grant are a direct and logical continuation of the applicant's previous work exploring the link )etween CMTX and the mutations in the genes controlling gap junction proteins; they build on previous efforts to correlate functional deficits at the cellular and subcellular level with specific mutations and with phenotypic variability. The first two specific aims will use electrophysiologic techniques to examine the loss of Cx32 function resulting from alterations in gating and permeability of mutant forms of Cx32. The third specific aim will again use electrophysiologic techniques to evaluate the possibility that mutations in Cx32 may turn this protein into a suicide channel, leading to disrupted function in cells in which it is expressed. The fourth specific aim utilizes targeted gene replacement to examine the differential effects of two mutant forms of Cx32. The support of a K02 Independent Scientist Award will insure that the applicant is able to maintain at least 75% effort in basic science research while at the same time benefiting from the unique scientific environment of the Department of Neuroscience of the Albert Einstein College of Medicine. These factors will provide an opportunity for continued intellectual and technical development of the PI during this critical early period of development as a physician- scientist engaged in an independent program of translational research.

X 连锁腓骨肌萎缩症 (CMTX) 是一种与突变相关的遗传性周围神经病 间隙连接蛋白连接蛋白 32 (Cx32)。该提案的中心原则是，修改 Cx32 形成的离子通道的功能特性可引起 CMTX。此外，我们建议 了解突变与疾病之间的联系，我们必须探索诱导突变的具体性质 通道门控、渗透性和地层控制方面的缺陷。尽管特定之间存在关联 离子通道和神经肌肉疾病的突变通常是引人注目的，其背后的机制 临床测量、形态学检查或流行病学可能无法揭示缺陷。研究 ）本次拨款中提出的内容是申请人之前探索该链接的工作的直接且合乎逻辑的延续 ）CMTX 与控制间隙连接蛋白的基因突变之间；他们以之前的努力为基础 将细胞和亚细胞水平的功能缺陷与特定突变和表型相关联 可变性。前两个具体目标将使用电生理技术来检查 Cx32 功能的丧失 这是由于 Cx32 突变体的门控和通透性改变所致。第三个具体目标将再次使用 电生理技术评估 Cx32 突变可能将该蛋白转变为自杀的可能性 通道，导致表达该通道的细胞功能受损。第四个具体目标利用有针对性的 基因替换以检查两种 Cx32 突变形式的差异效应。 K02的支持 独立科学家奖将确保申请人能够在基础科学上保持至少75%的努力 进行研究的同时受益于该系独特的科学环境 阿尔伯特·爱因斯坦医学院的神经科学。这些因素将为继续 在作为医生发展的关键早期阶段，PI 的智力和技术发展 从事独立转化研究项目的科学家。

项目成果

Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations.

遗传性痉挛性截瘫是 GJA12/GJC2 突变的一种新表型。

• DOI: 10.1093/brain/awn328
• 发表时间: 2009-02-01
• 期刊: Brain : a journal of neurology
• 作者: Jennifer L. Orthmann;E. Salsano;C. Abrams;A. Bizzi;G. Uziel;M. Freidin;E. Lamantea;M. Zeviani;S. Scherer;D. Pareyson
• 通讯作者: D. Pareyson