Mitochondrial Localization of Human PANK2 and Hypotheses of Secondary Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration

: 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 bios...

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Bibliographic Details
Published in:Annals of the New York Academy of Sciences 2004-03, Vol.1012 (1), p.282-298
Main Authors: JOHNSON, MONIQUE A., KUO, YIEN MING, WESTAWAY, SHAWN K., PARKER, SUSAN M., CHING, KATHERINE H. L., GITSCHIER, JANE, HAYFLICK, SUSAN J.
Format: Article
Language:English
Subjects:
Animals
Antibodies - metabolism
Blotting, Western - methods
Brain - metabolism
brain iron
Cercopithecus aethiops
Cloning, Molecular - methods
CoA
COS Cells
Green Fluorescent Proteins
Hallervorden-Spatz syndrome
HeLa Cells
Humans
Immunohistochemistry - methods
Iron - metabolism
Luminescent Proteins - metabolism
Mice
Mitochondria - metabolism
mitochondrial localization
Mitochondrial Proteins - metabolism
Mutation
Neurodegenerative Diseases - genetics
Neurodegenerative Diseases - metabolism
pantothenate kinase
Phosphotransferases (Alcohol Group Acceptor) - genetics
Phosphotransferases (Alcohol Group Acceptor) - immunology
Phosphotransferases (Alcohol Group Acceptor) - metabolism
PKAN
Reverse Transcriptase Polymerase Chain Reaction - methods
RNA, Messenger - biosynthesis
Transfection
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Summary:: 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.
ISSN:0077-8923
1749-6632
DOI:10.1196/annals.1306.023