title: An isoform of hPANK2, deficient in pantothenate kinase-associated neurodegeneration, localizes to mitochondria.
abstract: Mutations in the human PANK2 gene have been shown to occur in autosomal-recessive pantothenate kinase-associated neurodegeneration, a syndrome originally described by Hallervorden and Spatz. The kinase catalyses the first and rate-limiting step in the biosynthesis of coenzyme A, a key molecule in energy metabolism. We have determined the exon-intron structure of the hPANK2 gene and identified two alternatively used first exons. The resulting transcripts encode distinct isoforms of hPANK2, one of which carries an N-terminal extension with a predicted mitochondrial targeting signal. An in vitro import assay and in vivo immunolocalization experiments demonstrate a mitochondrial localization of this isoform. We conclude that the symptoms observed in pantothenate kinase-associated neurodegeneration are caused by a deficiency of the mitochondrial isoform and postulate the existence of a complete intramitochondrial pathway for de novo synthesis of coenzyme A.
authors.affiliation: Institute of Human Genetics, GSF Research Centre for Environment and Health, D-85764 Neuherberg, Germany. hoertnagel@gsf.de
authors.forename: Konstanze
authors.initials: K
authors.lastname: Hörtnagel
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
mesh_terms: D000818:Animals; D019556:COS Cells; D003001:Cloning, Molecular; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA
chemical_list: D007527:Isoenzymes; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase