cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
15714522
DOI
10.1002/humu.20131
Knihovny.cz E-resources
- MeSH
- 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase deficiency MeSH
- White People genetics MeSH
- Betaine therapeutic use MeSH
- Point Mutation MeSH
- Ferredoxin-NADP Reductase deficiency genetics MeSH
- Fibroblasts enzymology pathology MeSH
- Genetic Therapy * MeSH
- Haplotypes genetics MeSH
- Homocysteine blood MeSH
- Homocystinuria blood classification drug therapy enzymology genetics pathology therapy MeSH
- Hydroxocobalamin therapeutic use MeSH
- Folic Acid therapeutic use MeSH
- Humans MeSH
- Mutation, Missense MeSH
- Brain pathology MeSH
- DNA Mutational Analysis MeSH
- Codon, Nonsense MeSH
- Polymerase Chain Reaction MeSH
- Polymorphism, Restriction Fragment Length MeSH
- Polymorphism, Genetic MeSH
- Recombinant Fusion Proteins physiology MeSH
- Sequence Deletion MeSH
- Amino Acid Substitution MeSH
- Genes, Synthetic MeSH
- Genetic Complementation Test MeSH
- Transfection MeSH
- Cell Line, Transformed enzymology pathology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase MeSH
- Betaine MeSH
- Ferredoxin-NADP Reductase MeSH
- Homocysteine MeSH
- Hydroxocobalamin MeSH
- Folic Acid MeSH
- methionine synthase reductase MeSH Browser
- Codon, Nonsense MeSH
- Recombinant Fusion Proteins MeSH
The cblE type of homocystinuria is a rare autosomal recessive disorder caused by impaired reductive activation of methionine synthase. Although earlier biochemical studies proposed that the methionine synthase enzyme might be activated by two different reducing systems, mutations were reported in only the methionine synthase reductase gene (MTRR) in cblE patients. The pathogenicity of MTRR mutations, however, has not yet been tested functionally. We report on nine patients of European origin affected by the cblE type of homocystinuria. They presented between 2 weeks and 3 years of age (median age 4 weeks) with anemia, which was macrocytic in only three patients, and with neurological involvement in all but two cases. Bone marrow examination performed in seven patients showed megaloblastic changes in all but one of them. All patients exhibited moderate to severe hyperhomocysteinemia (median plasma total homocysteine [Hcy] 92 mumol/L, range 44-169), while clearly reduced methionine was observed only in four cases. Pathogenic mutations were identified in both parental alleles of the MTRR gene in all patients. Five known (c.903+469T>C, c.1361C>T, c.1459G>A, c.1557-4_1557+3del7, and c.1622_1623dupTA) and three novel mutations (c.7A>T, c.1573C>T, and c.1953-6_1953-2del5) were detected. Importantly, transfection of fibroblasts of cblE patients with a wild-type MTRR minigene expression construct resulted in a significant approximately four-fold increase of methionine synthesis, indicating correction of the enzyme defect. Our study shows a link between a milder predominantly hematological presentation and homozygosity for the c.1361C>T mutation, but no other obvious genotype-phenotype correlation. The identification of mutations in the MTRR gene, together with restoration of methionine synthesis following MTRR minigene expression in cblE cells confirms that this disease is caused by defects in the MTRR gene.
Hum Mutat. 2005 Dec;26(6):590 PubMed
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