Molecular Foundations of the Myoclonus-Dystonia Syndrome

描述(申请人提供)：epsilon肌聚糖基因突变与一种中枢神经系统疾病--肌阵挛-肌张力障碍综合征(MDS，OMIM 159900，DYT11)有关。相比之下，其他肌聚糖家族成员的突变会导致四肢带状肌营养不良。MDS的发病时间通常在出生后的头20年。肌张力障碍，通常是颈部和/或作家抽筋，发生在许多但不是所有的患者。罕见的是，肌张力障碍可能是受影响的家庭成员疾病的唯一表型表现。外显性是不完整的，表现力在家庭内部和家庭之间都是可变的。到目前为止，几乎所有发表的突变都与过早终止密码子有关。母亲的印记已经被证明在老鼠和人类身上都发生了，结果是，当母亲传递突变的等位基因时，外显性会降低。当突变的等位基因从父亲那里遗传时，母体等位基因由于印记而失活会导致epsilon肌聚糖缺乏。DYT1和DYT11的相似之处(如表达不稳定、儿童期发病、不完全外显、成人发病时出现作家抽筋)提示它们在分子病理学上可能存在重叠。 从胚胎期到成年期，在神经(小脑皮质、纹状体、大脑皮质、丘脑、海马体)和非神经(肌肉、肝脏、肾脏、心脏)组织中均可检测到Epsilon肌聚糖。Epsilon肌聚糖的表达在肌肉中的发育规律最为显著，胚胎和出生后早期的表达水平比成人高出十倍以上。在成年人中，epsilon肌聚糖在大脑中的转录水平是肌肉的几倍，特别是小脑皮质。作为了解这种独特的肌聚糖在神经功能和肌张力障碍的病理生理学中的作用的下一步，我们建议建立epsilon肌聚糖基因敲除小鼠。此外，还将产生针对epsilon肌聚糖的抗体，用于这种独特的膜糖蛋白的神经解剖学和未来的功能研究。我们推测，epsilon肌糖蛋白与GABA受体共同定位于中枢神经系统中与GABA能终末相对的位置。

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.