Molecular Foundations of the Myoclonus-Dystonia Syndrome

肌阵挛-肌张力障碍综合征的分子基础

• 批准号: 6967443
• 负责人: MARK S LEDOUX
• 金额: $ 7.3万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6967443
• 关键词: GABA receptor; cytoskeletal proteins; dystonia; electron microscopy; family genetics; gene targeting; genetic disorder; genetically modified animals; genomic imprinting; glycoproteins; immunocytochemistry; laboratory mouse; membrane proteins; molecular pathology; myoclonus; neurons; protein localization; protein structure function; syndrome

DESCRIPTION (provided by applicant): Mutations in the gene for epsilon sarcoglycan are associated with a disorder of the central nervous system, the myoclonus-dystonia syndrome (MDS, OMIM 159900, DYT11). In contrast, mutations of other sarcoglycan family members lead to limb-girdle muscular dystrophies. The onset of MDS is usually in the first two decades of life. Dystonia, usually cervical and/or writer's cramp, occurs in many but not all patients. Rarely, dystonia may be the only phenotypic manifestation of the disease in an affected family member. Penetrance is incomplete and expressivity is variable both within and among families. Nearly all mutations published to date are associated with premature stop codons. Maternal imprinting has been shown to occur in both mice and humans and, as a result, reduced penetrance is seen when the mother passes on the mutant allele. When the mutant allele is inherited from the father, inactivation of the maternal allele due to imprinting leads to epsilon sarcoglycan deficiency. The similarities between DYT1 and DYT11 (e.g., variable expressivity, childhood onset, incomplete penetrance, writer's cramp presentation of adult-onset cases) suggests that there may be overlap in their molecular pathologies. Epsilon sarcoglycan can be detected in both neural (cerebellar cortex, striatum, cerebral cortex, thalamus, hippocampus) and non-neural (muscle, liver, kidney, heart) tissues from the embryo stage through adulthood. The developmental regulation of epsilon sarcoglycan expression is most striking in muscle with embryonic and early postnatal levels over ten times higher than those seen in adults. In adults, epsilon sarcoglycan transcript levels are several-fold higher in brain, particularly cerebellar cortex, than in muscle. As the next step towards understanding the role of this unique sarcoglycan in both neural function and the pathophysiology of dystonia, we propose to generate epsilon sarcoglycan knockout mice. In addition, antibodies to epsilon sarcoglycan will be produced for neuroanatomical and future functional studies of this unique membrane glycoprotein. We hypothesize that epsilon sarcoglycan co-localizes with GABA receptors opposite GABAergic terminals in the central nervous system.

描述（由申请人提供）：Epsilon sarcoglycan基因中的突变与中枢神经系统的疾病，Myoclonus-Dystonia综合征（MDS，OMIM 159900，DYT11）有关。相比之下，其他莎科聚糖家庭成员的突变导致肢体肌营养不良。 MD的发作通常在生命的前二十年。 肌张力障碍（通常是宫颈和/或作家的抽筋）发生在许多但不是所有患者中。 肌张力障碍很少是受影响家庭成员中该疾病的唯一表型表现。渗透性是不完整的，并且在家庭内部和家庭之间的表现性都有变化。迄今为止，几乎所有发布的突变都与早产停止密码子有关。孕产妇的印迹已显示出在小鼠和人类中都发生，因此，当母亲通过突变等位基因时，出现了降低的渗透率。当突变等位基因是从父亲那里继承的时，由于烙印而导致孕产妇等位基因的失活导致Epsilon Sarcoglycan缺乏症。 Dyt1和Dyt11之间的相似性（例如，可变表达性，儿童发作，不完全的渗透率，作者对成人发作病例的抽筋表现）表明其分子病理可能存在重叠。 可以在神经（小脑皮层，纹状体，脑皮质，丘脑，丘脑，海马）和非神经（肌肉，肝，肾脏，肾脏，心脏）组织中检测到Epsilon sarcoglycan。 epsilon sarcoglycan表达的发育调节在胚胎和早期产后水平的肌肉中最引人注目，超过十倍，比成年人高十倍。 在成年人中，大脑（尤其是小脑皮层）比肌肉中的Epsilon Sarcoglycan转录水平高几倍。 作为了解这种独特的肌酸酯在神经功能和肌张力障碍病理生理学中的作用的下一步，我们建议生成epsilon sarcoglycan敲除小鼠。此外，将针对这种独特的膜糖蛋白的神经解剖学和未来功能研究产生乳糖核糖的抗体。我们假设epsilon sarcoglycan与中枢神经系统中GABA能末端的GABA受体共定位。