TY - JOUR
T1 - Molecular analysis of methylmalonyl-CoA mutase deficiency
T2 - Identification of three missense mutations in mut0 patients
AU - Mikami, Hitoshi
AU - Ogasawara, Masahito
AU - Matsubara, Yoichi
AU - Kikuchi, Masahiro
AU - Miyabayashi, Shigeaki
AU - Kure, Shigeo
AU - Narisawa, Kuniaki
PY - 1999
Y1 - 1999
N2 - 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.
AB - 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.
KW - Adenosylcobalamin
KW - Methylmalonic acidemia
KW - Methylmalonyl-CoA mutase
KW - Mutation
KW - Organic aciduria
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U2 - 10.1007/s100380050103
DO - 10.1007/s100380050103
M3 - Article
C2 - 9929975
AN - SCOPUS:0032912482
VL - 44
SP - 35
EP - 39
JO - Jinrui idengaku zasshi. The Japanese journal of human genetics
JF - Jinrui idengaku zasshi. The Japanese journal of human genetics
SN - 1434-5161
IS - 1
ER -