Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: molecular genetic and enzymatic characterization of 76 patients

Human Mutation
Patricie BurdaMatthias R Baumgartner

Abstract

5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common inherited disorder of folate metabolism and causes severe hyperhomocysteinaemia. To better understand the relationship between mutation and function, we performed molecular genetic analysis of 76 MTHFR deficient patients, followed by extensive enzymatic characterization of fibroblasts from 72 of these. A deleterious mutation was detected on each of the 152 patient alleles, with one allele harboring two mutations. Sixty five different mutations (42 novel) were detected, including a common splicing mutation (c.1542G>A) found in 21 alleles. Using an enzyme assay in the physiological direction, we found residual activity (1.7%-42% of control) in 42 cell lines, of which 28 showed reduced affinity for nicotinamide adenine dinucleotide phosphate (NADPH), one reduced affinity for methylenetetrahydrofolate, five flavin adenine dinucleotide-responsiveness, and 24 abnormal kinetics of S-adenosylmethionine inhibition. Missense mutations causing virtually absent activity were found exclusively in the N-terminal catalytic domain, whereas missense mutations in the C-terminal regulatory domain caused decreased NADPH binding and disturbed inhibition by S-adenosylmeth...Continue Reading

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Citations

Jun 1, 2016·Journal of Inherited Metabolic Disease·Wyatt W Yue
Jun 2, 2016·Cellular and Molecular Life Sciences : CMLS·Rebecca A JacksonEe Sin Chen
Dec 23, 2016·Briefings in Bioinformatics·Mark T Mc AuleyJ Enrique Salcedo-Sora
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Aug 5, 2021·Indian Journal of Pediatrics·Vykuntaraju K GowdaSanjay K Shivappa

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