title: Mutation eliminating mitochondrial leader sequence of methylmalonyl-CoA mutase causes muto methylmalonic acidemia.
abstract: Methylmalonyl-CoA mutase (EC 5.4.99.2) is a mitochondrial matrix enzyme whose activity is deficient in the inherited disorder methylmalonic acidemia. Previous studies on primary fibroblast cell lines from patients with methylmalonic acidemia have delineated a variety of biochemical phenotypes underlying this disorder. One cell line with primary mutase apoenzyme deficiency exhibited a particularly unusual phenotype; it expressed an abnormally small and unstable immunoreactive protein, which was not imported by mitochondria. We now report cloning and sequencing of the cDNA encoding this mutant protein. The mutation is a single base change, a cytosine----thymine transition, which introduces an amber termination codon at position 17 within the mitochondrial leader sequence. The immunoreactive protein produced by these cells reflects translation from AUG codons downstream from this termination codon and, hence, lacks a mitochondrial leader peptide. This mutation represents a complex prototype for a class of mutations in which absence of the mitochondrial targeting sequence leads to absence of a functioning gene product.
authors.affiliation: Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030.
authors.forename: F D
authors.initials: FD
authors.lastname: Ledley
authors.forename: R
authors.initials: R
authors.lastname: Jansen
authors.forename: S U
authors.initials: SU
authors.lastname: Nham
authors.forename: W A
authors.initials: WA
authors.lastname: Fenton
authors.forename: L E
authors.initials: LE
authors.lastname: Rosenberg
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics; D005091:Exons; D005796:Genes; D006801:Humans; D007535:Isomerases / Q000235:genetics*; D008314:Malonates / Q000378:metabolism*; D008764:Methylmalonic Acid / Q000378:metabolism*; D008765:Methylmalonyl-CoA Mutase / Q000172:deficiency / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D015345:Oligonucleotide Probes; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D014176:Protein Biosynthesis; D021382:Protein Sorting Signals / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D008314:Malonates; D015345:Oligonucleotide Probes; D021382:Protein Sorting Signals; D008764:Methylmalonic Acid; D004247:DNA; D007535:Isomerases; D008765:Methylmalonyl-CoA Mutase