Brief Data Reports
The methionine synthase (Mtr) gene maps to
proximal mouse Chromosome 13
Zhi-Xin Zhang, Daniel Leclerc, Roy Gravel,
Departments of Human Genetics, Pediatrics and Biology, McGill
University-Montreal Children’s Hospital Research Institute, 4060 Ste.
Catherine St. West, Room 242, Montreal, Canada H3Z 2Z3
Received: 26 April 1997 / Accepted: 3 June 1997
Locus name: methionine synthase or 5-methyltetrahydrofolate-
Locus symbol: Mtr
Map position: proximal–D13Mit1–1.06 cM ± 1.06 SE–Mtr, D13Bir4,
D13Bir6–1.06 ± 1.06–D13Abb1e–2.13 ± 1.49–D13Bir7–distal
Method of mapping: Mtr was localized by RFLP analysis of 96
animals from an interspecific backcross panel ((C57BL/6JEi ×
× SPRET/Ei) provided by The Jackson Laboratory,
Bar Harbor, Me. (BSS panel) .
Database deposit information: The data are available from the
Mouse Genome Database, accession number MGD-JNUM-39061.
Molecular reagents: A 1095-bp mouse cDNA was obtained by
reverse transcription/PCR of mouse liver RNA, with degenerate
oligonucleotides based on regions of homology within the methi-
onine synthase sequences of lower organisms. The two primers
(D1730 and D1733), as described by Leclerc et al. , were success-
ful in amplifying both human and mouse cDNAs. The PCR products
from both species were subcloned and sequenced; they showed 89%
identity. The mouse cDNA was labeled by random priming and hy-
bridized to Southern blots of EcoRI-digested mouse genomic DNA.
Allele detection: Allele detection was performed by RFLP analysis
of an EcoRI polymorphism. The C57BL/6J strain has alleles of
approximately 13 kb, while the Mus spretus strain has alleles of
approximately 9 kb and 4 kb. A constant band of approximately
0.5 kb was seen in both strains.
Previously identified homologs: Human MTR has been mapped to
chromosomal band 1q43 by fluorescence in situ hybridization [2–4].
Discussion: Methionine synthase (EC 126.96.36.199, 5-methylte-
trahydrofolate-homocysteine methyltransferase) catalyzes homo-
cysteine remethylation to methionine, with 5-methyltetra-
hydrofolate as the methyl donor and methylcobalamin as a co-
factor. Nutritional deficiencies and genetic defects in homocyste-
ine metabolism result in varying degrees of hyperhomocystein-
emia. Dramatic elevations in plasma and urinary homocysteine
levels are associated with the inborn error of metabolism, homo-
cystinuria. Consequent to the recent isolation of the human cDNA
for methionine synthase [2–4], two groups of investigators have
identified mutations in methionine synthase in homocystinuric pa-
tients [2, 5]. Mild elevations in plasma homocysteine are thought
to be a risk factor for both vascular disease and neural tube defects
[6–8]. A genetic variant in methylenetetrahydrofolate reductase
(MTHFR), the enzyme that synthesizes 5-methyltetrahydrofolate
for the methionine synthase reaction, is the most common genetic
determinant of hyperhomocysteinemia identified thus far . Mild
defects in the methionine synthase reaction are also potential candi-
dates for hyperhomocysteinemia and the associated multifactorial dis-
eases. A common variant has been reported for the human methionine
synthase gene, but its physiologic consequences have not yet been
determined [2, 4].
The mapping of the human MTR gene to 1q43 and of the mouse
gene to proximal Chromosome (Chr) 13 is consistent with previ-
ous findings of human/mouse homologies between these 2 chro-
mosomal regions; the human and mouse nidogen genes have been
mapped to 1q43 and proximal Chr 13, respectively .
Several genes have already been implicated in neural tube defects
in mice . Studies involving the mouse methionine synthase
gene will be useful in assessing the role of this important enzyme
in the development of birth defects and/or vascular disease.
Acknowledgments: The expert advice of Lucy Rowe (The Jackson Labo-
ratory Backcross DNA Panel Map Resource) and the clerical assistance of
Carolyn Mandel are gratefully acknowledged. This work was supported by
a grant from the Medical Research Council of Canada to the MRC Group
in Medical Genetics.
1. Rowe LB, Nadeau JH, Turner R, Frankel WN, Letts VA, Eppig JT, Ko
MSH, Thurston SJ, Birkenmeier EH (1994) Mamm Genome 5, 253–
2. Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, Ross M,
Eydoux P, Rosenblatt DS, Rozen R, Gravel RA (1996) Hum Mol
Genet 5, 1867–1874
3. Li YN, Gulati S, Baker PJ, Brody LC, Banerjee R, Kruger WD (1996)
Hum Mol Genet 5, 1851–1858
4. Chen LH, Liu M-L, Hwang H-Y, Chen L-S, Korenberg J, Shane B
(1997) J Biol Chem 272, 3628–3634
5. Gulati S, Baker P, Li YN, Fowler B, Kruger W, Brody LC, Banerjee
R (1996) Hum Mol Genet 5, 1859–1865
6. Boushey C, Beresford SAA, Omenn GS, Motulsky AG (1995) J Am
Med Assoc 274, 1049–1057
7. Steegers-Theunissen RPM, Boers GHJ, Trijbels FJM, Finkelstein JD,
Correspondence to: R. Rozen
Fig. 1. The localization of Mtr to proximal Chr 13. The markers are from
the BSS backcross panel. These data and references for mapping the other
loci are publicly available from The Jackson Laboratory Mapping Re-
source at the World Wide Web address: http://www.jax.org/resources/
© Springer-Verlag New York Inc. 1997Mammalian Genome 8, 787–797 (1997).