Alternative titles; symbols
HGNC Approved Gene Symbol: MCEE
SNOMEDCT: 1293018007;
Cytogenetic location: 2p13.3 Genomic coordinates (GRCh38) : 2:71,109,687-71,130,229 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p13.3 | Methylmalonyl-CoA epimerase deficiency | 251120 | Autosomal recessive | 3 |
By searching for sequences similar to prokaryotic lactoylglutathione lyases, followed by PCR of a liver cDNA library, Bobik and Rasche (2001) cloned MCEE. The deduced 176-amino acid protein contains an N-terminal mitochondrial targeting sequence.
Bobik and Rasche (2001) demonstrated that MCEE has DL-methylmalonyl-CoA racemase activity.
Bobik and Rasche (2001) determined that the MCEE gene contains 3 exons.
By genomic sequence analysis, Bobik and Rasche (2001) mapped the MCEE gene to chromosome 2.
Bikker et al. (2006) reported a 16-year-old female patient with persistent moderate methylmalonic aciduria. In vitro biochemical findings that comprised a decreased propionate incorporation into macromolecules in cultured fibroblasts and a fully normal activity of methylmalonyl-CoA mutase in the same cells were fully explained by deficiency of methylmalonyl-CoA epimerase. Bikker et al. (2006) identified a homozygous nonsense mutation in the MCEE gene (R47X; 608419.0001). Both parents were heterozygous for this mutation; they were found to excrete normal amounts of methylmalonic acid. The patient also had a DOPA-responsive dystonia which was shown to result from homozygous mutation in the sepiapterin reductase gene (182125.0005). Bikker et al. (2006) suggested that deficiency of methylmalonyl-CoA epimerase does not have a large clinical impact or could even be considered a nondisease. A functional role of methylmalonyl-CoA epimerase was the object of debate for a long time (Montgomery et al., 1983).
Dobson et al. (2006) reported a patient homozygous for the R47X mutation. She had mild methylmalonic aciduria.
In a patient with methylmalonyl-CoA epimerase deficiency, Waters et al. (2016) identified compound heterozygous mutations in the MCEE gene: the R47X mutation and a novel intronic splice site mutation (c.379-644A-G; 608419.0002). The mother was heterozygous for the splice site mutation; the father was unavailable for study and was presumed to carry the R47X mutation. Gene expression studies in patient fibroblasts demonstrated that the splice site mutation resulted in an alternate transcript with inclusion of an additional 92 basepairs between exons 2 and 3 and a premature stop codon. Studies in patient fibroblasts demonstrated reduced propionate incorporation, which was corrected with cellular complementation with fibroblasts from patients in the mut, cblA, and cblB complementation classes, but not with fibroblasts from a patient in the MCEE complementation class.
Bikker et al. (2006) described a female patient born to consanguineous Caucasian parents with methylmalonyl-CoA epimerase deficiency (251120) and dystonia due to sepiapterin reductase deficiency (612716). The methylmalonyl-CoA epimerase deficiency was found to be caused by homozygosity for a 139C-T transition in exon 2 of the MCEE gene that resulted in an arg47 to ter substitution (R47X). This nonsense mutation was predicted to result in an inactive epimerase enzyme, since the transcript would probably be rapidly degraded by nonsense-mediated decay; alternatively, if the transcript were stable, only a small part of it would be translated, because of the early termination signal. The patient was homozygous for a second mutation, in the SPR gene resulting in sepiapterin reductase deficiency (182125.0005); both parents were heterozygous for both mutations. Both genes map to chromosome 2. However, the sepiapterin reductase mutation in this family was a missense mutation, thus excluding the possibility of a contiguous gene syndrome. The clinical presentation of this patient closely resembled that described in a case of sepiapterin reductase deficiency with dystonia as the most prominent symptom. Bikker et al. (2006) suggested that since this patient was homozygous for 2 mutations, it was likely that methylmalonyl-CoA epimerase deficiency does not have a large clinical impact, or could even be considered as a nondisease.
Dobson et al. (2006) reported a patient previously identified as belonging to the cobalamin A (cblA) complementation group (251100) but lacking mutations in the affected gene MMAA (607481). The patient's fibroblasts had normal levels of adenosylcobalamin compared to controls, whereas other cblA cell lines typically had reduced levels of the cofactor. The patient also had a milder form of methylmalonic aciduria than usually observed in cblA patients. The patient was homozygous for the R47X mutation in MCEE. One sib, also with mild methylmalonic aciduria, was also homozygous for the mutation. Both parents and one other sib were heterozygous. To assess the impact of isolated MCEE deficiency in cultured cells, HeLa cells were transfected with siRNA against MCEE. The reduced level of MCEE mRNA resulted in reduction of [(14)C]-propionate incorporation into cellular macromolecules. However, siRNA led to only a small reduction in pathway activity, suggesting that previously postulated nonenzymatic conversion of D- to L-methylmalonyl-CoA may contribute to some flux through the pathway.
In a patient with methylmalonyl-CoA epimerase deficiency, Waters et al. (2016) identified compound heterozygous mutations in the MCEE gene: the R47X mutation (608419.0001) in exon 2 and an intronic splice site mutation (c.379-644A-G). The R47X mutation was identified by exon sequencing and the splicing mutation by RNA studies. The mother was heterozygous for the splice site mutation; the father was unavailable for study and was presumed to carry the R47X mutation. Gene expression studies in patient fibroblasts demonstrated that the c.379-644A-G mutation resulted in an alternate transcript with inclusion of an additional 92 basepairs between exons 2 and 3 and a premature stop codon. Studies in patient fibroblasts demonstrated reduced propionate incorporation, which was corrected with cellular complementation with fibroblasts from patients in the mut, cblA, and cblB complementation classes, but not with fibroblasts from a patient in the MCEE complementation class.
Bikker, H., Bakker, H. D., Abeling, N. G. G. M., Poll-The, B. T., Kleijer, W. J., Rosenblatt, D. S., Waterham, H. R., Wanders, R. J. A., Duran, M. A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria. Hum. Mutat. 27: 640-643, 2006. [PubMed: 16752391] [Full Text: https://doi.org/10.1002/humu.20373]
Bobik, T. A., Rasche, M. E. Identification of the human methylmalonyl-CoA racemase gene based on the analysis of prokaryotic gene arrangements: implications for decoding the human genome. J. Biol. Chem. 276: 37194-37198, 2001. [PubMed: 11481338] [Full Text: https://doi.org/10.1074/jbc.M107232200]
Dobson, C. M., Gradinger, A., Longo, N., Wu, X., Leclerc, D., Lerner-Ellis, J., Lemieux, M., Belair, C., Watkins, D., Rosenblatt, D. S., Gravel, R. A. Homozygous nonsense mutations in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: a novel cause of mild methylmalonic aciduria. Molec. Genet. Metab. 88: 327-333, 2006. [PubMed: 16697227] [Full Text: https://doi.org/10.1016/j.ymgme.2006.03.009]
Montgomery, J. A., Mamer, O. A., Scriver, C. R. Metabolism of methylmalonic acid in rats: Is methylmalonyl-coenzyme A racemase deficiency symptomatic in man? J. Clin. Invest. 72: 1937-1947, 1983. [PubMed: 6643681] [Full Text: https://doi.org/10.1172/JCI111158]
Waters, P. J., Thuriot, F., Clarke, J. T., Gravel, S., Watkins, D., Rosenblatt, D. S., Levesque, S. Methylmalonyl-CoA epimerase deficiency: a new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene. Molec. Genet. Metab. Rep. 9: 19-24, 2016. [PubMed: 27699154] [Full Text: https://doi.org/10.1016/j.ymgmr.2016.09.001]