The Mmachc gene is required for pre-implantation embryogenesis in the mouse

Patients with mutations in MMACHC have the autosomal recessive disease of cobalamin metabolism known as cblC. These patients are unable to convert cobalamin into the two active forms, methylcobalamin and adenosylcobalamin and consequently have elevated homocysteine and methylmalonic acid in blood an...

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Bibliographic Details
Published in:Molecular genetics and metabolism 2014-07, Vol.112 (3), p.198-204
Main Authors: Moreno-Garcia, Maira A., Pupavac, Mihaela, Rosenblatt, David S., Tremblay, Michel L., Jerome-Majewska, Loydie A.
Format: Article
Language:English
Subjects:
Alleles
Amino Acid Metabolism, Inborn Errors - genetics
Animals
Carrier Proteins - genetics
Cobalamin
Embryonic Development - genetics
Female
Gene Order
Gene Targeting
Genetic Vectors - genetics
Genotype
Hyperhomocysteinemia - genetics
Male
Mice
Mmachc
Phenotype
Pre-implantation
Ratio distortion
Trophectoderm
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Summary:Patients with mutations in MMACHC have the autosomal recessive disease of cobalamin metabolism known as cblC. These patients are unable to convert cobalamin into the two active forms, methylcobalamin and adenosylcobalamin and consequently have elevated homocysteine and methylmalonic acid in blood and urine. In addition, some cblC patients have structural abnormalities, including congenital heart defects. MMACHC is conserved in the mouse and shows tissue and stage-specific expression pattern in midgestation stage embryos. To create a mouse model of cblC we generated a line of mice with a gene-trap insertion in intron 1 of the Mmachc gene, (MmachcGt(AZ0348)Wtsi). Heterozygous mice show a 50% reduction of MMACHC protein, and have significantly higher levels of homocysteine and methylmalonic acid in their blood. The MmachcGt allele was inherited with a transmission ratio distortion in matings with heterozygous animals. Furthermore, homozygous MmachcGt embryos were not found after embryonic day 3.5 and these embryos were unable to generate giant cells in outgrowth assays. Our findings confirm that cblC is modeled in mice with reduced levels of Mmachc and suggest an early requirement for Mmachc in mouse development. •Generation of mice with mutation in Mmachc.•Heterozygous mice have increased levels of homocysteine and methylmalonic acid.•Homozygous mutant embryos arrest pre-implantation.•A previously unknown role for Mmachc in the trophectoderm lineage and implantation.
ISSN:1096-7192
1096-7206
DOI:10.1016/j.ymgme.2014.05.002