Molecular analysis of methylmalonyl-CoA mutase deficiency: Identification of three missense mutations in mut0 patients

Hitoshi Mikami, Masahito Ogasawara, Yoichi Matsubara, Masahiro Kikuchi, Shigeaki Miyabayashi, Shigeo Kure, Kuniaki Narisawa

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Genetic defects in the methylmalonyl-CoA mutase (MCM) gene cause methylmalonic acidemia (MMA). Only three mutations have been reported among Oriental patients to date. We studied fibroblast cell lines established from three Japanese patients with MCM deficiency. Enzymatic study showed that these patients had the mut0 type of MMA. Nucleotide sequencing of MCM cDNAs identified three missense mutations: a T to A change at nucleotide position 2082, which results in an amino acid substitution of Glu669 for valine (V669E); a T to A change at position 1179 with the corresponding amino acid substitution of Asp368 for valine (V368D); and a G to A change at position 1182 with the corresponding amino acid substitution of His369 for arginine (R369H). Each of the three missense mutations abolished MCM activity according to a transient expression study. Alignment of these mutations with a recently reported homology model of human MCM allowed us to speculate on the effect of these nonconservative amino acid substitutions on MCM activity: V368D and R369H affected residues in the β/α-(TIM-) barrel domain, on one of the two α-helices that form the dimer interface, while V669E altered a residue in the adenosylcobalamin-binding domain in the C terminus.

Original languageEnglish
Pages (from-to)35-39
Number of pages5
JournalJournal of Human Genetics
Volume44
Issue number1
DOIs
Publication statusPublished - 1999

Keywords

  • Adenosylcobalamin
  • Methylmalonic acidemia
  • Methylmalonyl-CoA mutase
  • Mutation
  • Organic aciduria

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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