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Biochemical analysis of patients with mutations in MTHFD1 and a diagnosis of methylenetetrahydrofolate dehydrogenase 1 deficiency
- Source :
- Molecular genetics and metabolism. 130(3)
- Publication Year :
- 2020
-
Abstract
- MTHFD1 is a trifunctional protein containing 10-formyltetrahydrofolate synthetase, 5,10-methenyltetrahydrofolate cyclohydrolase and 5,10-methylenetetrahydrofolate dehydrogenase activities. It is encoded by MTHFD1 and functions in the cytoplasmic folate cycle where it is involved in de novo purine synthesis, synthesis of thymidylate and remethylation of homocysteine to methionine. Since the first reported case of severe combined immunodeficiency resulting from MTHFD1 mutations, seven additional patients ascertained through molecular analysis have been reported with variable phenotypes, including megaloblastic anemia, atypical hemolytic uremic syndrome, hyperhomocysteinemia, microangiopathy, infections and autoimmune diseases. We determined the level of MTHFD1 expression and dehydrogenase specific activity in cell extracts from cultured fibroblasts of three previously reported patients, as well as a patient with megaloblastic anemia and recurrent infections with compound heterozygous MTHFD1 variants that were predicted to be deleterious. MTHFD1 protein expression determined by Western blotting in fibroblast extracts from three of the patients was markedly decreased compared to expression in wild type cells (between 4.8 and 14.3% of mean control values). MTHFD1 expression in the fourth patient was approximately 44% of mean control values. There was no detectable methylenetetrahydrofolate dehydrogenase specific activity in extracts from any of the four patients. This is the first measurement of MTHFD1 function in MTHFD1 deficient patients and confirms the previous molecular diagnoses.
- Subjects :
- 0301 basic medicine
Hyperhomocysteinemia
Homocysteine
Endocrinology, Diabetes and Metabolism
MTHFD1
030105 genetics & heredity
Folic Acid Deficiency
Compound heterozygosity
Biochemistry
Minor Histocompatibility Antigens
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Endocrinology
Atypical hemolytic uremic syndrome
Genetics
Medicine
Humans
Megaloblastic anemia
Molecular Biology
Cells, Cultured
Methylenetetrahydrofolate Dehydrogenase (NADP)
Methionine
business.industry
Fibroblasts
medicine.disease
Molecular biology
3. Good health
chemistry
Methylenetetrahydrofolate dehydrogenase
Case-Control Studies
Mutation
Severe Combined Immunodeficiency
business
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 10967206
- Volume :
- 130
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Molecular genetics and metabolism
- Accession number :
- edsair.doi.dedup.....f377896eee8f8ad4f740bc0c7140adc5