Human Molecular Genetics Advance Access originally published online on January 5, 2009
Human Molecular Genetics 2009 18(6):1058-1064; doi:10.1093/hmg/ddn441
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Paroxysmal non-kinesigenic dyskinesia is caused by mutations of the MR-1 mitochondrial targeting sequence
1 Unit of Molecular Neurogenetics—Pierfranco and Luisa Mariani Center for the Study of Children’s Mitochondrial Disorders, National Neurological Institute ‘Carlo Besta’, Milan, Italy 2 Department of Experimental Medicine and Diagnostics, University of Ferrara, Ferrara, Italy 3 Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy 4 Division of Neurosciences, Public Health Hospital, Rovigo, Italy
* To whom correspondence should be addressed at: Unit of Molecular Neurogenetics, National Neurological Institute ‘Carlo Besta’, via Temolo 4, 20126 Milan, Italy. Tel: +39 0223942630; Fax: +39 0223942619; Email: zeviani{at}tin.it, zeviani{at}istituto-besta.it
Received November 19, 2008; Accepted December 23, 2008
Paroxysmal non-kinesigenic dyskinesia (PNKD) is an autosomal-dominant movement disorder characterized by attacks of dystonia, chorea and athetosis. Myofibrillogenesis regulator-1 (MR-1), the gene responsible for PNKD, is transcribed into three alternatively spliced forms: long (MR-1L), medium (MR-1M) and small (MR-1S). Two mutations, A7V and A9V, were previously discovered in the N-terminal region common to MR-1L and MR-1S. We now found a third mutation, A33P, in a new PNKD patient in the same region. Contrary to previous reports, we show here that the mutation-free MR-1M is localized in the Golgi apparatus, ER and plasma membrane, whereas both MR-1L and MR-1S isoforms are mitochondrial proteins, imported into the organelle thanks to a 39 amino acid-long, N-terminal mitochondrial targeting sequence (MTS). The MTS, which contains all three PNKD mutations, is then cleaved off the mature proteins before their insertion in the inner mitochondrial membrane. Therefore, mature MR-1S and MR-1L of PNKD patients are identical to those of normal subjects. We found no difference in import efficiency and protein maturation between wild-type and mutant MR-1 variants. These results indicate that PNKD is due to a novel disease mechanism based on a deleterious action of the MTS.