Congenital Myasthenic Syndromes: Pathogenic Mechanisms

先天性肌无力综合征：发病机制

基本信息

批准号：
8610360
负责人：
RICARDO Anibal MASELLI
金额：
$ 32.58万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8610360
关键词：
Acetylcholinesterase Adult Affect Agrin Animal Model Biological Biopsy Blood capillaries Candidate Disease Gene Catalytic Domain Cell Line Cells Choline O-Acetyltransferase Cholinergic Receptors Chromosomal Duplication Clinical Clinical Data Clinical Research Code Collagen Complex Congenital Myasthenic Syndromes DNA DNA Resequencing DNA Sequence DNA analysis Defect Detection Disease Electron Microscopy Elements Enzymes Evaluation Failure Genealogical Tree Genes Genetic Polymorphism Goals Immunohistochemistry Induced Mutation Inherited Intercostal Muscles Knowledge Laboratory Study Laminin Lead Life Mammalian Cell Membrane Methods Microelectrodes Mind Missense Mutation Modality Molecular Abnormality Molecular Diagnosis Molecular Target Muscle Muscle Weakness Muscle-Specific Kinase Mutate Mutation Nature Neuromuscular Diseases Neuromuscular Junction Pathogenesis Patients Performance Phenotype Phosphotransferases Physical Examination Population Population Control Proteins RNA Recording of previous events Reporting Research Single Nucleotide Polymorphism Sodium Channel Splice-Site Mutation Syndrome System Tail Techniques Testing Time alpha Bungarotoxin capillary clinical phenotype comparative genomic hybridization effective therapy fetal genetic association microdeletion mutant neuromuscular transmission new technology novel peripheral membrane protein 43K prevent protein function public health relevance receptor research clinical testing response transmission process voltage

项目摘要

DESCRIPTION (provided by applicant): Congenital Myasthenic Syndromes (CMS), which are a heterogeneous group of inborn diseases characterized by impaired transmission of electrical impulses at the neuromuscular junction (NMJ), result from defects in one of multiple genes involved with the function of the NMJ. During the last century, defects in genes encoding the adult acetylcholine receptor (AChR) subunit genes (CHRNA1, CHRNB1, CHRND, CHRNE), and the acetylcholinesterase (AChE) collagenic tail (COLQ) were shown to cause several forms of CMS. During the last decade the genes encoding six other molecular targets, including the enzyme choline acetyltransferase (CHAT), rapsyn (RAPSN), the voltage-gated muscle sodium channel (SCN4A), the muscle-specific kinase (MUSK), Dok-7 (DOK7) and the fetal subunit of the AChR (CHRNG), have been demonstrated to be implicated in the pathogenesis of other types of CMS. We recently reported an additional target for mutations causing CMS, which is the gene encoding laminin beta 2 (LAMB2), bringing up the number of genes associated with CMS, to a total of twelve. Several other defective genes are likely to be involved in the pathogenesis of CMS since in a large number of patients affected with CMS no abnormalities can be found in the genes listed above. The proposed research is driven by the hypothesis that an inborn defect of any essential protein of the NMJ, for which no effective substituting molecule is available, can result in a CMS. However, a particularly challenging problem for detecting genetic defects causing CMS and preventing the reoccurrence of these diseases is the fact that there is a very large number of possible candidate genes and only very few clues in the CMS phenotype that can assist with the search for the causative mutation. In response to this challenge, the first specific aim of this project is to utilize conventional and novel methods of identification of the various types of CMS and their underlying genetic defects using clinical data; a special type of muscle biopsy, which includes intracellular microelectrode studies; electron microscopy of the NMJ and immunohistochemistry; as well as conventional and novel techniques for DNA analysis. The second specific aim of the project is to conduct expression studies in mammalian cell lines to characterize the effects of the discovered mutations. The long term goal of the project is to gain a better understating of the pathogenesis of CMS which may lead to effective forms of treatment for these neuromuscular disorders.

描述（由申请人提供）：先天性肌无力综合症 (CMS) 是一组异质性先天性疾病，其特征是神经肌肉接头 (NMJ) 电脉冲传输受损，是由与神经肌肉接头功能相关的多个基因之一的缺陷引起的。国家医学杂志。在上个世纪，编码成人乙酰胆碱受体 (AChR) 亚基基因（CHRNA1、CHRNB1、CHRND、CHRNE）和乙酰胆碱酯酶 (AChE) 胶原尾 (COLQ) 的基因缺陷被证明会导致多种形式的 CMS。在过去十年中，编码其他六种分子靶标的基因，包括胆碱乙酰转移酶 (CHAT)、rapsyn (RAPSN)、电压门控肌肉钠通道 (SCN4A)、肌肉特异性激酶 (MUSK)、Dok-7（ DOK7) 和 AChR (CHRNG) 胎儿亚基已被证明与其他类型 CMS 的发病机制有关。我们最近报道了引起 CMS 的突变的另一个目标，即编码层粘连蛋白 β 2 (LAMB2) 的基因，使与 CMS 相关的基因数量达到 12 个。其他几个缺陷基因可能与 CMS 的发病机制有关，因为在大量患有 CMS 的患者中，在上述基因中未发现异常。这项研究的假设是，任何 NMJ 必需蛋白的先天缺陷（没有有效的替代分子）都可能导致 CMS。然而，检测引起 CMS 的遗传缺陷并预防这些疾病复发的一个特别具有挑战性的问题是，存在大量可能的候选基因，而 CMS 表型中只有很少的线索可以帮助寻找致病突变。为了应对这一挑战，该项目的第一个具体目标是利用临床数据利用传统和新颖的方法来识别各种类型的 CMS 及其潜在的遗传缺陷；一种特殊类型的肌肉活检，包括细胞内微电极研究； NMJ 的电子显微镜和免疫组织化学；以及 DNA 分析的传统和新技术。该项目的第二个具体目标是在哺乳动物细胞系中进行表达研究，以表征所发现的突变的影响。该项目的长期目标是更好地了解 CMS 的发病机制，这可能会导致这些神经肌肉疾病的有效治疗形式。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Presynaptic congenital myasthenic syndrome with a homozygous sequence variant in LAMA5 combines myopia, facial tics, and failure of neuromuscular transmission.

LAMA5 纯合序列变异导致突触前先天性肌无力综合征，伴有近视、面部抽搐和神经肌肉传递障碍。

DOI：
发表时间：
2017-08
期刊：
影响因子：
0
作者：
Maselli, Ricardo A;Arredondo, Juan;Vázquez, Jessica;Chong, Jessica X;University of Washington Center for Mendelian Genomics;Bamshad, Michael J;Nickerson, Deborah A;Lara, Marian;Ng, Fiona;Lo, Victoria L;Pytel, Peter;McDonald, Craig M
通讯作者：
McDonald, Craig M

Choline Acetyltransferase Mutations Causing Congenital Myasthenic Syndrome: Molecular Findings and Genotype-Phenotype Correlations.

胆碱乙酰转移酶突变导致先天性肌无力综合征：分子发现和基因型-表型相关性。

DOI：
发表时间：
2015-09
期刊：
影响因子：
3.9
作者：
Arredondo, Juan;Lara, Marian;Gospe Jr, Sídney M;Mazia, Claudio G;Vaccarezza, Maria;Garcia;Bowe, Constance M;Chang, Celia H;Mezei, Michelle M;Maselli, Ricardo A
通讯作者：
Maselli, Ricardo A

Congenital myasthenic syndrome associated with epidermolysis bullosa caused by homozygous mutations in PLEC1 and CHRNE.

与 PLEC1 和 CHRNE 纯合突变引起的大疱性表皮松解症相关的先天性肌无力综合征。

DOI：
发表时间：
2011-11
期刊：
影响因子：
3.5
作者：
Maselli, R A;Arredondo, J;Cagney, O;Mozaffar, T;Skinner, S;Yousif, S;Davis, R R;Gregg, J P;Sivak, M;Konia, T H;Thomas, K;Wollmann, R L
通讯作者：
Wollmann, R L

A presynaptic congenital myasthenic syndrome attributed to a homozygous sequence variant in LAMA5.

一种突触前先天性肌无力综合征，归因于 LAMA5 的纯合序列变异。

DOI：
发表时间：
2018-02
期刊：
影响因子：
5.2
作者：
Maselli, Ricardo A;Arredondo, Juan;Vázquez, Jessica;Chong, Jessica X;Bamshad, Michael J;Nickerson, Deborah A;Lara, Marian;Ng, Fiona;Lo, Victoria Lee;Pytel, Peter;McDonald, Craig M
通讯作者：
McDonald, Craig M

Presynaptic congenital myasthenic syndrome with altered synaptic vesicle homeostasis linked to compound heterozygous sequence variants in RPH3A.

突触前先天性肌无力综合征，突触小泡稳态改变与 RPH3A 复合杂合序列变异有关。

DOI：
发表时间：
2018
期刊：
影响因子：
2
作者：
Maselli, Ricardo A;Vázquez, Jessica;Schrumpf, Leah;Arredondo, Juan;Lara, Marian;Strober, Jonathan B;Pytel, Peter;Wollmann, Robert L;Ferns, Michael
通讯作者：
Ferns, Michael