The 1298(A→C) Mutation of Methylenetetrahydrofolate Reductase Should Be Designated to the 1289 Position of the Gene

Abstract

To the Editor:van der Put et al. (1998xA second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects. van der Put, NMJ, Fons, G, Stevens, EMB, Smeitink, JAM, Trijbels, FJM, Eskes, TKAB, van den Heuvel, LP et al. Am J Hum Genet. 1998; 62: 1044–1051Abstract | Full Text | Full Text PDF | PubMed | Scopus (1114)See all References1998) recently reported that a second common mutation within the gene coding for the enzyme methylenetetrahydrofolate reductase (MTHFR; E.C.1.5.1.20) results in significantly reduced catalytic activity. This mutation is important because MTHFR plays a significant role in the metabolism of folate and, ultimately, of homocysteine, which is implicated as a risk factor for neural-tube defects (Copp et al. 1990xThe embryonic development of mammalian neural tube defects. Copp, AJ, Brook, FA, Estibeiro, JP, Shum, ASW, and Cockroft, DL. Prog Neurobiol. 1990; 35: 363–403Crossref | PubMed | Scopus (229)See all References1990). van der Put et al. (1998xA second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects. van der Put, NMJ, Fons, G, Stevens, EMB, Smeitink, JAM, Trijbels, FJM, Eskes, TKAB, van den Heuvel, LP et al. Am J Hum Genet. 1998; 62: 1044–1051Abstract | Full Text | Full Text PDF | PubMed | Scopus (1114)See all References1998) designated this mutation—MTHFR 1298(A→C)—as changing a glutamate into an alanine residue. A review of the human MTHFR mRNA sequence (GenBank accession number U09806) shows that this mutation is not present in the human sequence at position 1298 but may, in fact, be mutation 1289(A→C). There are two reasons why this may be so. First, the nucleotide at 1298 is a T (fig. 1fig. 1). Second, the authors report that this mutation, 1298C, destroys an MboII restriction site. The recognition site for MboII is GAAGANNNNNNN/N/. There is no MboII restriction site at 1298; however, there is one at 1289 in the human MTHFR sequence (fig. 1fig. 1). The enzyme MboII is expected to cut between nucleotides 1297 and 1298, whereas the mutation they describe is likely to be at position 1289. Although this does not affect the results of their study, it is important to accurately designate mutations to the proper nucleotide position, thereby avoiding errors in subsequent research concerning this important gene.Figure 1MboII restriction site on human MTHFR (GenBank accession U09806). MboII recognizes GAAGA (upper nucleotide sequence). MTHFR 1298C (lower sequence) abolishes the MboII site. Sequence data were obtained from GenBank (accession number U09806). The lower sequence is identical to the GenBank sequence.View Large Image | View Hi-Res Image | Download PowerPoint Slide