Molecular Foundations of the Myoclonus-Dystonia Syndrome

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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.