Human Molecular Genetics Advance Access published online on January 5, 2009
Human Molecular Genetics, 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 "C. 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, Italy 4 Division of Neurosciences, Public Health Hospital, Rovigo, Italy
* Correspondence to: Massimo Zeviani, MD, PhD, Unit of Molecular Neurogenetics, National Neurological Institute "Carlo Besta", via Temolo 4, 20133 Milan, Italy, FAX +39-02-23942619, Phone +39-02-23942630, E-mail: zeviani{at}tin.it, zeviani{at}istituto-besta.it, URL: www.mitopedia.org
Received November 19, 2008; Revised December 23, 2008; Accepted December 23, 2008
PNKD is an autosomal dominant movement disorder characterized by attacks of dystonia, chorea and athetosis. 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 aminoacid-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 wt 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.