Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders.
Methionine synthase catalyzes the remethylation of homocysteine to methionine in a methylcobalamin-dependent reaction. We used specific regions of homology within the methionine synthase sequences of several lower organisms to clone a human methionine synthase cDNA by a combination of RT-PCR and inverse PCR. The enzyme is 1265 amino acids in length and contains the seven residue structure-based sequence fingerprint identified for cobalamin-containing enzymes. The gene was localized to chromosome 1q43 by the FISH technique. We have identified one missense mutation and a 3 bp deletion in patients of the cblG complementation group of inherited homocysteine/folate disorders by SSCP and sequence analysis, as well as an amino acid substitution present in high frequency in the general population. We discuss the possibility that a mild deficiency of methionine synthase activity could be associated with mild hyperhomocysteinemia, a risk factor for cardiovascular disease and possibly neural tube defects.
Leclerc
D
D
MRC Group in Medical Genetics, Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
Campeau
E
E
Goyette
P
P
Adjalla
C E
CE
Christensen
B
B
Ross
M
M
Eydoux
P
P
Rosenblatt
D S
DS
Rozen
R
R
Gravel
R A
RA
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics* / Q000302:isolation & purification; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016415:Sequence Alignment; D014805:Vitamin B 12 / Q000235:genetics / Q000378:metabolism*
D018076:DNA, Complementary; D006710:Homocysteine; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D014805:Vitamin B 12