Genetic heterogeneity among patients with methylcobalamin deficiency. Definition of two complementation groups, cblE and cblG.

Abstract

A number of patients with megaloblastic anemia and homocystinuria associated with low levels of methylcobalamin synthesis in cultured cells have been recognized. Methionine biosynthesis by intact cells, as determined by incorporation of label from 5-I14Clmethyl-tetrahydrofolate into acid-precipitable material, was deficient in cultured skin fibroblasts that were derived from all of these patients. In one group of patients, activity of the methylcobalamin-dependent enzyme, methionine synthase, in cell extracts was within the normal range when the enzyme was assayed under standard conditions. In a second group of patients, methionine synthase activity was decreased under the same assay conditions. Genetic complementation analysis demonstrated the existence of two complementation classes that corresponded to these two groups of patients. The designation cblE has previously been proposed for the mutation in a patient with methylcobalamin deficiency and normal methionine synthase activity. We propose the designation cblG for the mutation in those patients with methylcobalamin deficiency and decreased synthase activity. The results of these studies suggest that the products of at least two loci are required for cobalamin-dependent methionine biosynthesis in mammalian cells.

Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase

“…The identity of the deduced gene was confirmed by detection of mutations in methionine synthase reductase in cblE patients [20]. Human patients with inherited syndromes of impaired methionine synthase activity caused by defective methionine synthase reductase are characterized by elevated plasma total homocysteine or hyperhomocyst (e)inemia, decreased plasma methionine, megaloblastic anemia and delayed development, as well as a variety of other neurological ailments, including neuropathy, movement disorders, nystagmus, seizures and dementia [21][22][23][24][25].…”

The cblD Defect Causes Either Isolated or Combined Deficiency of Methylcobalamin and Adenosylcobalamin Synthesis

“…Automated sequence analysis was performed using an ABI Prism 3700 sequencer (Applied Biosystems) essentially as recommended by the manufacturer. The entire MTRR coding sequence with its flanking 5Ј-and 3Ј-untranslated regions was amplified in five overlapping segments employing cDNA and sequenced as described previously (25) except for a 5Ј-coding region (exons [1][2][3][4][5]. This region contains alternative isoforms, and therefore exons 1-5 were analyzed by sequencing of PCR products derived from genomic DNA.…”

The molecular basis of glutamate formiminotransferase deficiency

“…Complementation analysis indicated the presence of the two distinct groups, reflecting mutations at separate loci. As a result, ceIl lines with methylcobalamin deficiency but with normal methionine biosynthesis under standard reducing conditions were given the designation cbiE while ceIllines with methylcobalamin deficiency but with decreased methionine biosynthesis under standard reducing conditions was designated cblG (Watkins and Rosenblatt, 1988). Patients diagnosed with cblG disease have errors in methionine synthase, while patients diagnosed with cbiE have errors in methionine synthase reductase.…”