title: The Mmachc gene is required for pre-implantation embryogenesis in the mouse.
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.
authors.affiliation: Department of Human Genetics, McGill University, 1205 Avenue Docteur Penfield, N5/13, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Maira A
authors.initials: MA
authors.lastname: Moreno-Garcia
authors.affiliation: Department of Human Genetics, McGill University, 1205 Avenue Docteur Penfield, N5/13, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Pupavac
authors.affiliation: 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.
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
authors.affiliation: Department of Biochemistry, McGill University, Goodman Cancer Research Center, 1160 Avenue Pine, Montreal, Quebec, Canada.
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.affiliation: 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.
authors.forename: Loydie A
authors.initials: LA
authors.lastname: Jerome-Majewska
mesh_terms: D000483:Alleles; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D023061:Gene Order; D018390:Gene Targeting; D005822:Genetic Vectors / Q000235:genetics; D005838:Genotype; D020138:Hyperhomocysteinemia / Q000235:genetics; D008297:Male; D051379:Mice; D010088:Oxidoreductases; D010641:Phenotype
chemical_list: D002352:Carrier Proteins; C570224:Mmachc protein, mouse; D010088:Oxidoreductases
keywords: Cobalamin; Mmachc; Pre-implantation; Ratio distortion; Trophectoderm