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

Abstract

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.

Genetic polymorphisms associated with pancreatic cancer survival: a genome‐wide association study

“…MCEE catalyzes the interconversion of d ‐ and l ‐methylmalonyl‐CoA during the degradation of branched chain amino acids, odd chain‐length fatty acids and other metabolites. Mutations in this gene result in methylmalonyl‐CoA epimerase deficiency, which is presented as mild to moderate methylmalonic aciduria . Whether these two genes play any role in cancer is currently unknown.…”

“…Mutations in this gene result in methylmalonyl-CoA epimerase deficiency, which is presented as mild to moderate methylmalonic aciduria. 37 Whether these two genes play any role in cancer is currently unknown. Network analysis identified several signaling pathways that are significantly associated with survival, such as the G betagamma and CXCR4 signaling pathways.…”

Structural and mechanistic comparisons of the metal-binding members of the vicinal oxygen chelate (VOC) superfamily

“…MMCE catalyzes the conversion of (2R)-methylmalonyl-CoA to (2S)-methylmalonyl-CoA, the substrate for the B 12 -dependent methylmalonyl-CoA mutase. MMCE is widely found and essential in the breakdown of odd-chain fatty acids and branched amino acids [33][34][35]. The Propionibacteriumshermanii enzyme is activated to the greatest extent by Co 2+ , but also by Ni 2+ , Mn 2+ , and Zn 2+ , and the rat liver enzyme by Fe 2+ , Mn 2+ , and Co 2+ [36,37].…”

Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under l-DOPA, 5-HTP and BH4 Trials

“…The mild methylmalonic aciduria and the decrease in [14C] propionate incorporation were attributed to the MCEE gene mutation. Five other cases were reported without clinical feature (Gradinger et al 2007). A functional role for MCEE or epimerase has been debated in humans (Montgomery et al 1983).…”

“…In contrast to the (2R)-methylmalonylcoenzyme A ([2R]-methylmalonyl-CoA) mutase (MIM 609058) deficiency which leads to a high excretion of methylmalonic acid, MCEE deficiency is responsible for a mild increase of methylmalonic aciduria, probably because of an in vivo shunt from the propionate-to-succinate pathway. Mutations in the MCEE gene were described in only five patients, identified by a moderate methylmalonic acid excretion in urine (Gradinger et al 2007). On the contrary, sepiapterin reductase deficiency (SRD) is a severe autosomal recessive disorder of tetrahydrobiopterin (BH4) metabolism (Friedman et al 2012).…”