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

Maira A Moreno-Garcia; Mihaela Pupavac; David S Rosenblatt; Michel L Tremblay; Loydie A Jerome-Majewska

doi:10.1016/j.ymgme.2014.05.002

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

Mol Genet Metab. 2014 Jul;112(3):198-204. doi: 10.1016/j.ymgme.2014.05.002. Epub 2014 May 14.

Authors

Maira A Moreno-Garcia¹, Mihaela Pupavac¹, David S Rosenblatt², Michel L Tremblay³, Loydie A Jerome-Majewska⁴

Affiliations

¹ Department of Human Genetics, McGill University, 1205 Avenue Docteur Penfield, N5/13, Montreal, Quebec H3A 1B1, Canada.
² Department of Human Genetics, McGill University, 1205 Avenue Docteur Penfield, N5/13, Montreal, Quebec H3A 1B1, Canada; Department of Pediatrics, McGill University, Research Institute, Place Toulon, 4060 Ste. Catherine West PT 420, Montreal Children's Hospital, Montreal, Quebec H3Z 2Z3, Canada.
³ Department of Biochemistry, McGill University, Goodman Cancer Research Center, 1160 Avenue Pine, Montreal, Quebec, Canada.
⁴ Department of Human Genetics, McGill University, 1205 Avenue Docteur Penfield, N5/13, Montreal, Quebec H3A 1B1, Canada; Department of Pediatrics, McGill University, Research Institute, Place Toulon, 4060 Ste. Catherine West PT 420, Montreal Children's Hospital, Montreal, Quebec H3Z 2Z3, Canada; Department of Anatomy and Cell Biology, McGill University, Strathcona Anatomy and Dentistry Building, 3640 University Street, Montreal, Quebec H3A2B2, Canada. Electronic address: loydie.majewska@mcgill.ca.

PMID: 24889031
DOI: 10.1016/j.ymgme.2014.05.002

Abstract

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, (Mmachc(Gt(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 Mmachc(Gt) allele was inherited with a transmission ratio distortion in matings with heterozygous animals. Furthermore, homozygous Mmachc(Gt) 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.

Keywords: Cobalamin; Mmachc; Pre-implantation; Ratio distortion; Trophectoderm.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Amino Acid Metabolism, Inborn Errors / genetics
Animals
Carrier Proteins / genetics*
Embryonic Development / genetics*
Female
Gene Order
Gene Targeting
Genetic Vectors / genetics
Genotype
Hyperhomocysteinemia / genetics
Male
Mice
Oxidoreductases
Phenotype

Substances

Carrier Proteins
Mmachc protein, mouse
Oxidoreductases

Supplementary concepts

Methylmalonic acidemia

Grants and funding

15078/Canadian Institutes of Health Research/Canada