J. Biol. Chem., Vol. 264, Issue 25, 14597-14600, Sep, 1989
Reversion of the maple syrup urine disease phenotype of impaired branched chain alpha-ketoacid dehydrogenase complex activity in fibroblasts from an affected child
S Litwer, WJ Herring and DJ Danner
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322.
Branched chain alpha-ketoacid dehydrogenase is a heteroprotein complex of
mitochondria and commits the branched chain alpha-ketoacids to their
catabolic fate. Inherited nuclear mutations in humans decrease the activity
of this complex and result in maple syrup urine disease. Here we
demonstrate the restoration of branched chain alpha-ketoacid dehydrogenase
activity to fibroblasts from a child with this disorder by transfection
with a cDNA for the prebranched chain acyltransferase. Prior to
transfection these fibroblasts contained the prebranched chain
acyltransferase gene but failed to transcribe the gene and thus lacked the
protein. Regulation of the restored complex by phosphorylation mechanisms
resembles that of wild-type cells. These results describe a human cell
modeling system for testing engineered proteins and support the possibility
of gene replacement therapy for this human disorder.
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