Complementation studies in the cblA class of inborn error of cobalamin metabolism: evidence for interallelic complementation and for a new complementation class (cblH)

Watkins, David; Matiaszuk, Nora; Rosenblatt, David S.

doi:10.1136/jmg.37.7.510

Cited by 50 publications

(26 citation statements)

References 15 publications

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“…Patients were assigned to complementation groups (cblA-H, mut) based on the outcome of cell fusion experiments and the apparent biochemical defect involved [16][17][18]. The cblE complementation group was shown to result from defective reactivation of methionine synthase [19].…”

Section: Introductionmentioning

confidence: 99%

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

Elmore

Leclerc

et al. 2007

Molecular Genetics and Metabolism

122

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Hyperhomocyst(e)inemia is a metabolic derangement that is linked to the distribution of folate pools, which provide one-carbon units for biosynthesis of purines and thymidylate and for remethylation of homocysteine to form methionine. In humans, methionine synthase deficiency results in the accumulation of methyltetrahydrofolate at the expense of folate derivatives required for purine and thymidylate biosynthesis. Complete ablation of methionine synthase activity in mice results in embryonic lethality. Other mouse models for hyperhomocyst(e)inemia have normal or reduced levels of methyltetrahydrofolate and are not embryonic lethal, although they have decreased ratios of AdoMet/AdoHcy and impaired methylation. We have constructed a mouse model with a gene trap insertion in the Mtrr gene specifying methionine synthase reductase, an enzyme essential for the activity of methionine synthase. This model is a hypomorph, with reduced methionine synthase reductase activity, thus avoiding the lethality associated with the absence of methionine synthase activity. Mtrr gt/gt mice have increased plasma homocyst(e)ine, decreased plasma methionine, and increased tissue methyltetrahydrofolate. Unexpectedly, Mtrr gt/gt mice do not show decreases in the AdoMet/AdoHcy ratio in most tissues. The different metabolite profiles in the various genetic mouse models for hyperhomocysteinemia may be useful in understanding biological effects of elevated homocyst(e)ine.

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Section: Introductionmentioning

confidence: 99%

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

Elmore

Leclerc

et al. 2007

Molecular Genetics and Metabolism

122

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“…Mut and cblB fibroblasts complemented the genetic defect in WG2278 (p=0.0022 and p=0.0023 respectively). This patient had shown variable complementation with fibroblasts from the cblA group and was initially considered to be an atypical member of this complementation class (Watkins et al, 2000). Mut, cblA, and cblB fibroblasts complemented the genetic defect in WG2084 (p=0.001, p=0.0003, and p=0.0001 respectively).…”

Section: Complementation Analysismentioning

confidence: 99%

“…In this method the +1 position is the A of the ATG translation initiation codon. (Watkins et al, 2000). Statistical significance was determined using Student's t-test.…”

Section: Mutation Detectionmentioning

confidence: 99%

“…This study was approved by the Research Ethics Board of the Royal Victoria Hospital, Montreal, Quebec, Canada. Incorporation of label from [ 14 C]propionate into cellular macromolecules (a measure of MCM activity) and synthesis of cobalamin coenzyme derivatives from [ 57 Co]CNCbl were measured in all patient fibroblast lines (Watkins et al, 2000).…”

Section: Patients and Controlsmentioning

confidence: 99%

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Atypical methylmalonic aciduria: frequency of mutations in the methylmalonyl CoA epimerase gene (MCEE)

et al. 2007

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Methylmalonic aciduria is known to result from defects in the enzyme methylmalonyl CoA mutase (MCM) (mut complementation group) and from defects in the synthesis of the MCM cofactor adenosylcobalamin (cblA, cblB, cblC, cblD, and cblF groups). Two patients who excrete methylmalonic acid have recently been shown to have a homozygous nonsense mutation in the gene coding for methylmalonyl CoA epimerase (MCEE). To further understand the cause of methylmalonic acid excretion, the MCEE gene was sequenced in 229 patients with elevations of methylmalonic acid excretion for which no cause was known. Mutations in MCEE were detected in five patients: two patients homozygous for c.139C>T, p.R47X, one patient homozygous for c.178A>C, p.K60Q, and two patients heterozygous for c.427C>T, p.R143C. Fusion of fibroblast lines from two patients homozygous for c.139C>T, p.R47X did not result in correction of [ 14 C]propionate incorporation toward control values while the defect in these fibroblasts was complemented by mut, cblA, and cblB fibroblasts. Infection with wild-type MCEE cDNA resulted in correction of the biochemical phenotype in cells from both patients.

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“…At least two other genetic entities in the above pathway can be associated with isolated methylmalonic acidemia, cblD (variant 2) deficiency [44] and cblH deficiency [45]. The biochemical and genetic etiology of these disorders has not yet been determined.…”

Section: Other Lesionsmentioning

confidence: 99%

Genetic and genomic systems to study methylmalonic acidemia

Chandler

Venditti

2005

Molecular Genetics and Metabolism

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Methylmalonic acidemia (MMAemia) is the biochemical hallmark of a group of genetic metabolic disorders that share a common defect in the ability to convert methylmalonyl-CoA into succinylCoA. This disorder is due to either a mutant methylmalonyl-CoA mutase apoenzyme or impaired synthesis of adenosylcobalamin, the cofactor for this enzyme. In this article, we will provide an overview of the pathways disrupted in these disorders, discuss the known metabolic blocks with a particular focus on molecular genetics, and review the use of selected model organisms to study features of methylmalonic acidemia.

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Complementation studies in the cblA class of inborn error of cobalamin metabolism: evidence for interallelic complementation and for a new complementation class (cblH)

Cited by 50 publications

References 15 publications

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

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

Atypical methylmalonic aciduria: frequency of mutations in the methylmalonyl CoA epimerase gene (MCEE)

Genetic and genomic systems to study methylmalonic acidemia

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