Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 2; pp. 400 - 405
• Main Authors: Field, Martha S., Kamynina, Elena, Watkins, David, Rosenblatt, David S., Stover, Patrick J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.01.2015; National Acad Sciences
• Subjects: Amino Acid Substitution; Anemia; Anemia, Megaloblastic - genetics; Anemia, Megaloblastic - metabolism; Biological Sciences; Biosynthesis; Cell Line; Cell Nucleus - metabolism; Codon, Nonsense; Deoxyribonucleic acid; DNA; DNA Damage; Fibroblasts - metabolism; Humans; Metabolic Networks and Pathways; Metabolism; Methylenetetrahydrofolate Dehydrogenase (NADP) - chemistry; Methylenetetrahydrofolate Dehydrogenase (NADP) - deficiency; Methylenetetrahydrofolate Dehydrogenase (NADP) - genetics; Minor Histocompatibility Antigens; Mutant Proteins - chemistry; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Phenotype; Point Mutation; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - metabolism; Thymidine Monophosphate - biosynthesis; folate; thymidylate; MTHFD1; SCID; megaloblastic anemia

Significance These studies have identified that human genetic mutations, which impair the function of the folate-dependent enzyme methylene tetrahydrofolate dehydrogenase I (MTHFD1), depress rates of de novo thymidylate synthesis, elevate uracil levels in human DNA, and increase genome instability....