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Human Molecular Genetics, 2003, Vol. 12, No. 3 321-327
© 2003 Oxford University Press

An isoform of hPANK2, deficient in pantothenate kinase-associated neurodegeneration, localizes to mitochondria

Konstanze Hörtnagel1,*, Holger Prokisch2,3 and Thomas Meitinger1,3

1Institute of Human Genetics, GSF Research Centre for Environment and Health, D-85764 Neuherberg, Germany, 2Institute of Physiological Chemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-Universität Munich, D-81377 Munich, Germany and 3Institute of Human Genetics, Technical University of Munich, D-81675 Munich, Germany

Received October 7, 2002; Accepted November 29, 2002

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.

* To whom correspondence should be addressed. Tel: +49 8931873320; Fax: +49 8931873297; Email: hoertnagel{at}gsf.de


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