Mitochondrial Localization of Human PANK2 and Hypotheses of Secondary Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration
MONIQUE A. JOHNSON
Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
Search for more papers by this authorYIEN MING KUO
Howard Hughes Medical Institute and Departments of Medicine and Pediatrics, University of California, San Francisco, California, USA
Search for more papers by this authorSHAWN K. WESTAWAY
Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
Search for more papers by this authorSUSAN M. PARKER
Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
Search for more papers by this authorKATHERINE H. L. CHING
Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
Search for more papers by this authorJANE GITSCHIER
Howard Hughes Medical Institute and Departments of Medicine and Pediatrics, University of California, San Francisco, California, USA
Search for more papers by this authorCorresponding Author
SUSAN J. HAYFLICK
Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
Departments of Pediatrics and Neurology, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
Address for correspondence: Susan J. Hayflick, Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland, OR 97239. Voice: 503-494-6866; fax: 503-494-4411. [email protected]Search for more papers by this authorMONIQUE A. JOHNSON
Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
Search for more papers by this authorYIEN MING KUO
Howard Hughes Medical Institute and Departments of Medicine and Pediatrics, University of California, San Francisco, California, USA
Search for more papers by this authorSHAWN K. WESTAWAY
Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
Search for more papers by this authorSUSAN M. PARKER
Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
Search for more papers by this authorKATHERINE H. L. CHING
Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
Search for more papers by this authorJANE GITSCHIER
Howard Hughes Medical Institute and Departments of Medicine and Pediatrics, University of California, San Francisco, California, USA
Search for more papers by this authorCorresponding Author
SUSAN J. HAYFLICK
Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
Departments of Pediatrics and Neurology, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
Address for correspondence: Susan J. Hayflick, Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland, OR 97239. Voice: 503-494-6866; fax: 503-494-4411. [email protected]Search for more papers by this authorAbstract
Abstract: Mutations in the pantothenate kinase 2 gene (PANK2) lead to pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome). This neurodegenerative disorder is characterized by iron accumulation in the basal ganglia. Pantothenate kinase is the first enzyme in the biosynthesis of coenzyme A from pantothenate (vitamin B5). PANK2, one of four human pantothenate kinase genes, is uniquely predicted to be targeted to mitochondria. We demonstrate mitochondrial localization of PANK2 and speculate on mechanisms of secondary iron accumulation in PKAN. Furthermore, PANK2 uses an unconventional translational start codon, CUG, which is polymorphic in the general population. The variant sequence, CAG (allele frequency: 0.05), leads to skipping of the mitochondrial targeting signal and cytosolic localization of PANK2. This common variant may cause mitochondrial dysfunction and impart susceptibility to late-onset neurodegenerative disorders with brain iron accumulation, including Parkinson's disease.
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