Molecular Foundations of the Myoclonus-Dystonia Syndrome

描述（由申请人提供）：epsilon肌聚糖基因突变与中枢神经系统疾病肌阵挛-肌张力障碍综合征（MDS, OMIM 159900, DYT11）相关。相反，其他肌聚糖家族成员的突变会导致肢带肌营养不良症。MDS的发病通常在生命的头20年。肌张力障碍，通常是颈椎和/或作家痉挛，发生在许多但不是所有的患者。很少，肌张力障碍可能是唯一的表现型表现的疾病在一个受影响的家庭成员。外显性是不完整的，表达性在家族内部和家族之间都是可变的。迄今为止发表的几乎所有突变都与过早终止密码子有关。母体印记已被证明在小鼠和人类中都存在，因此，当母亲将突变等位基因传递给后代时，外显率会降低。当突变等位基因从父亲遗传时，由于印迹导致母亲等位基因失活导致epsilon肌聚糖缺乏。DYT1和DYT11之间的相似之处（例如，可变表达，儿童期发病，不完全外显，成年发病病例的作家痉挛表现）表明它们的分子病理可能存在重叠。

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.