title: Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration.
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 B(5)). 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.
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland 97239, USA.
authors.forename: Monique A
authors.initials: MA
authors.lastname: Johnson
authors.forename: Yien Ming
authors.initials: YM
authors.lastname: Kuo
authors.forename: Shawn K
authors.initials: SK
authors.lastname: Westaway
authors.forename: Susan M
authors.initials: SM
authors.lastname: Parker
authors.forename: Katherine H L
authors.initials: KH
authors.lastname: Ching
authors.forename: Jane
authors.initials: J
authors.lastname: Gitschier
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hayflick
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular / Q000379:methods; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007501:Iron / Q000378:metabolism*; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014162:Transfection
chemical_list: D000906:Antibodies; D008164:Luminescent Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D007501:Iron; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase