Homozygous nonsense mutation in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: A novel cause of mild methylmalonic aciduria

Dobson, C M; Gradinger, Abigail B.; Longo, Nicola; Wu, Xiaodong; Leclerc, Daniel; Lerner‐Ellis, Jordan; Lemieux, Melissa; Belair, Caroline; Watkins, David; Rosenblatt, David S.; Gravel, Roy A.

doi:10.1016/j.ymgme.2006.03.009

Cited by 38 publications

(45 citation statements)

References 21 publications

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“…However, it is not clear that the methylmalonic aciduria in these patients is consistently associated with clinical illness; if it is in fact associated there appears to be a large range in phenotype. The patient WG2278, reported by Dobson et al (2006) had severe metabolic acidosis, but her sibling, as well as one of the patients reported here (WG2797) were clinically asymptomatic despite being homozygous for the same nonsense mutation. The serious clinical findings in patient WG2084 seem all to be associated with this patient's sepiapterin reductase deficiency (Bikker et al, 2006).…”

Section: Discussionmentioning

confidence: 61%

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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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Section: Discussionmentioning

confidence: 61%

“…WG2278 was identified previously by Dobson et al (2006) and WG2084 was identified simultaneously by our group and by Bikker et al (2006). […”

Section: Complementation Analysismentioning

confidence: 96%

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

et al. 2007

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“…Many of the patient mutations which cause the generally more severe mut 0 subtype of disease occur within the substrate‐binding domain, whereas mutations within the cofactor‐binding domain often result in the usually later onset mut − disease subtype which at least in vitro is Cbl responsive . Mutation of MCEE, the enzyme directly upstream of MUT in the propionate catabolic pathway, as well as in SUCLG1 or SUCLA2 the genes encoding the heterodimeric enzyme succinate‐CoA ligase immediately downstream of MUT, also result in disease including MMAuria of milder degree.…”

Section: The Mitochondrial Cobalamin Pathwaymentioning

confidence: 99%

Vitamin B₁₂, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation

Froese

Fowler

Baumgartner

2019

J of Inher Metab Disea

307

187

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Vitamin B12 (cobalamin, Cbl) is a nutrient essential to human health. Due to its complex structure and dual cofactor forms, Cbl undergoes a complicated series of absorptive and processing steps before serving as cofactor for the enzymes methylmalonyl‐CoA mutase and methionine synthase. Methylmalonyl‐CoA mutase is required for the catabolism of certain (branched‐chain) amino acids into an anaplerotic substrate in the mitochondrion, and dysfunction of the enzyme itself or in production of its cofactor adenosyl‐Cbl result in an inability to successfully undergo protein catabolism with concomitant mitochondrial energy disruption. Methionine synthase catalyzes the methyl‐Cbl dependent (re)methylation of homocysteine to methionine within the methionine cycle; a reaction required to produce this essential amino acid and generate S‐adenosylmethionine, the most important cellular methyl‐donor. Disruption of methionine synthase has wide‐ranging implications for all methylation‐dependent reactions, including epigenetic modification, but also for the intracellular folate pathway, since methionine synthase uses 5‐methyltetrahydrofolate as a one‐carbon donor. Folate‐bound one‐carbon units are also required for deoxythymidine monophosphate and de novo purine synthesis; therefore, the flow of single carbon units to each of these pathways must be regulated based on cellular needs. This review provides an overview on Cbl metabolism with a brief description of absorption and intracellular metabolic pathways. It also provides a description of folate‐mediated one‐carbon metabolism and its intersection with Cbl at the methionine cycle. Finally, a summary of recent advances in understanding of how both pathways are regulated is presented.

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“…Methylmalonic acidemia may be due to a mutation in the gene CD320 (OMIM 606475) encoding the transcobalamin receptor TCBLR or a mutation in the methylmalonyl-CoA epimerase gene (OMIM 608419) (3, 4). …”

Section: Introductionmentioning

confidence: 99%

Heptadecanoylcarnitine (C17) a novel candidate biomarker for newborn screening of propionic and methylmalonic acidemias

Malvagia

Haynes²,

Grisotto

et al. 2015

Clinica Chimica Acta

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Background 3-hydroxypalmitoleoyl-carnitine (C16:1-OH) was recently reported to be elevated in acylcarnitine profile of propionic acidemia (PA) or methylmalonic acidemia (MMA) patients during expanded newborn screening (NBS). High levels of C16:1-OH, combined with other hydroxylated long chain acylcarnitines are related to long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). Methods The acylcarnitine profile of two LCHADD patients was evaluated using liquid chromatography-tandem mass spectrometric method. A specific retention time was reported for each hydroxylated long chain acylcarnitine. The same method was applied to some neonatal dried blood spots (DBS) from PA and MMA patients presenting abnormal C16:1-OH concentrations. Results The final retention time of the peak corresponding to C16:1-OH in LCHADD patients differed from those in MMA and PA patients. Heptadecanoylcarnitine (C17) has been identified as the novel biomarker specific for PA and MMA patients through high resolution mass spectrometry (Orbitrap) experiments. We found that 21 out of 23 neonates (22 MMA, and 1PA) diagnosed through the Tuscany region NBS program had significantly higher levels of C17 compared to levels detected in controls. Twenty-three maternal deficiencies (21 vitamin B12 deficiency, 1 homocystinuria and 1 gastrin deficiency) and 82 false positive for propionylcarnitine (C3) results were also analyzed. Conclusions This paper reports on the characterization of a novel biomarker able to detect propionate disorders during expanded newborn screening (NBS). The use of this new biomarker may improve the analytical performances of NBS programs especially in laboratories where second tier tests are not performed.

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Homozygous nonsense mutation in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: A novel cause of mild methylmalonic aciduria

Cited by 38 publications

References 21 publications

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

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

Vitamin B₁₂, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation

Heptadecanoylcarnitine (C17) a novel candidate biomarker for newborn screening of propionic and methylmalonic acidemias

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Homozygous nonsense mutation in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: A novel cause of mild methylmalonic aciduria

Cited by 38 publications

References 21 publications

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

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

Vitamin B12, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation

Heptadecanoylcarnitine (C17) a novel candidate biomarker for newborn screening of propionic and methylmalonic acidemias

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Product

Resources

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Vitamin B₁₂, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation