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Mitochondrial Localization of Human PANK2 and Hypotheses of Secondary Iron Accumulation in Pantothenate Kinase‐Associated Neurodegeneration
Author(s) -
JOHNSON MONIQUE A.,
KUO YIEN MING,
WESTAWAY SHAWN K.,
PARKER SUSAN M.,
CHING KATHERINE H. L.,
GITSCHIER JANE,
HAYFLICK SUSAN J.
Publication year - 2004
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1306.023
Subject(s) - neurodegeneration , biology , mitochondrion , mitochondrial disease , kinase , gene , genetics , microbiology and biotechnology , biochemistry , mitochondrial dna , medicine , disease , pathology
A bstract : 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.