Spectrum of mutations in<i>mut</i>methylmalonic acidemia and identification of a common Hispanic mutation and haplotype

Worgan, Lisa; Niles, Kirsten M.; Tirone, Jamie C.; Hofmann, Adam; Verner, Andrei; Sammak, Alya’a; Kucic, Terrence; Lepage, Pierre; Rosenblatt, David S.

doi:10.1002/humu.20258

Cited by 114 publications

(121 citation statements)

References 32 publications

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“…Radioactive incorporation studies with the N2 strain showed that C. elegans incorporates 1-[ 14 C]-propionate from propionate into protein in amounts similar to those seen in human cells [11 +/− 4 nmols/mg/18 hrs] [30] (Figure 3). Furthermore, a robust stimulation of incorporation was observed when hydroxycobalamin (OH-Cbl) was added to the medium in excess.…”

Section: Resultsmentioning

confidence: 89%

Propionyl-CoA and adenosylcobalamin metabolism in Caenorhabditis elegans: Evidence for a role of methylmalonyl-CoA epimerase in intermediary metabolism

Chandler¹,

Aswani²,

Tsai³

et al. 2006

Molecular Genetics and Metabolism

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We have utilized Caenorhabditis elegans to study human methylmalonic acidemia. Using bioinformatics, a full complement of mammalian homologues for the conversion of propionyl-CoA to succinyl-CoA in the genome of C. elegans, including propionyl-CoA carboxylase subunits A and B (pcca-1, pccb-1), methylmalonic acidemia cobalamin A complementation group (mmaa-1), co(I) balamin adenosyltransferase (mmab-1), MMACHC (cblc-1), methylmalonyl-CoA epimerase (mce-1) and methylmalonyl-CoA mutase (mmcm-1) were identified. To verify predictions that the entire intracellular adenosylcobalamin metabolic pathway existed and was functional, the kinetic properties of the C. elegans mmcm-1 were examined. RNA interference against mmcm-1, mmab-1, mmaa-1 in the presence of propionic acid revealed a chemical phenotype of increased methylmalonic acid; deletion mutants of mmcm-1, mmab-1 and mce-1 displayed reduced 1-[ 14 C]-propionate incorporation into macromolecules. The mutants produced increased amounts of methylmalonic acid in the culture medium, proving that a functional block in the pathway caused metabolite accumulation. Lentiviral delivery of the C. elegans mmcm-1 into fibroblasts derived from a patient with mut o class methylmalonic acidemia could partially restore propionate flux. The C. elegans mce-1 deletion mutant demonstrates for the first time that a lesion at the racemase step of methylmalonyl-CoA metabolism can functionally impair flux through the methylmalonyl-CoA mutase pathway and suggests that malfunction of MCEE may cause methylmalonic acidemia in humans. The C. elegans system we describe represents the first lower metazoan model organism of mammalian propionate spectrum disorders and demonstrates that mass spectrometry can be employed to study a small molecule chemical phenotype in C. elegans RNAi and deletion mutants.

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Section: Resultsmentioning

confidence: 89%

Propionyl-CoA and adenosylcobalamin metabolism in Caenorhabditis elegans: Evidence for a role of methylmalonyl-CoA epimerase in intermediary metabolism

Chandler¹,

Aswani²,

Tsai³

et al. 2006

Molecular Genetics and Metabolism

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“…Mutation p.R369H, on the other hand, may be of a double origin (haplotypes 2 and 5). The p.R369 codon contains a CpG dinucleotide, and p.R369H has been found in Turkish, Greek, Caucasian, Hispanic (Worgan et al 2006), and Korean (Jung et al 2005) populations.…”

Section: Resultsmentioning

confidence: 99%

“…To date, more than 100 disease-causing mutations in the human MUT gene have been reported (Ledley and Rosenblatt 1997;Acquaviva et al 2005;Martinez et al 2005), most of which seem to be unique or restricted to only a few pedigrees. However, there have been reports of specific mutations among various ethic groups, including p.G717V in blacks (Adjalla et al 1998), p.N219Y in Caucasians (Acquaviva et al 2001), and p.R108C in Hispanics (Worgan et al 2006). Ogasawara et al (1994b) reported a relatively high incidence of p.E117X in Japanese patients and, more recently, Kobayashi et al (2006) identified the plural occurrence of each of six mutations (p.L494X, p.R93H, p.E117X, p.R369H, p.G648D, and c.385 + 5G > A) in another Japanese population.…”

Section: Introductionmentioning

confidence: 99%

Mutation and haplotype analyses of the MUT gene in Japanese patients with methylmalonic acidemia

et al. 2006

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Methylmalonic acidemia (MMA) is caused by a deficiency in the activity of L-methylmalonylCoA mutase (MCM), a vitamin B12 (or cobalamin, Cbl)-dependent enzyme. Apoenzyme-deficient MMA (mut MMA) results from mutations in the nuclear gene MUT. Most of the MUT mutations are thought to be private or restricted to only a few pedigrees. Our group elucidated the spectrum of mutations of Japanese mut MMA patients by performing mutation and haplotype analyses in 29 patients with mut MMA. A sequence analysis identified mutations in 95% (55/58) of the disease alleles. Five mutations were relatively frequent (p.E117X, c.385 + 5G > A, p.R369H, p.L494X, and p.R727X) and four were novel (p.M1V, c.753_753 + 5delGGTATA, c.1560G > C, and c.2098_2099delAT). Haplotype analysis suggested that all of the frequent mutations, with the exception of p.R369H, were spread by the founder effect. Among 46 Japanese patients investigated in the present and previous studies, 76% (70/92) of the mutations were located in exons 2, 6, 8, and 13. This finding -that a limited number of mutations account for most of the mutations in Japanese mut MMA patients -is in contrast with results of a previous study in Caucasian patients.

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“…Splice site mutations, deletions, and insertions are relatively rare (Acquaviva et al, 2005;Worgan et al, 2006;Dündar et al, 2012). Most mutations have been found only once and are restricted to a single family, and there have been no mutation hotspots identified.…”

Section: Discussionmentioning

confidence: 99%

Mutation analysis and prenatal diagnosis for three families affected by isolated methylmalonic aciduria

Kong¹,

Shi²,

Liu³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. Isolated methylmalonic acidemia (MMA) is a genetically heterogeneous disorder caused mainly by deficiency of methylmalonyl-CoA mutase. In the present study, we analyzed MUT gene mutations in 3 Chinese couples with a birth history of isolated MMA. We also provided prenatal diagnoses for the detected mutation. Exons and exon-intron boundaries of the MUT gene were analyzed by polymerase chain reaction and direct sequencing. Prenatal genetic diagnoses were performed by chorionic villus sampling after the genotypes of parents were determined. Six heterozygous mutations in the MUT gene were identified in the 3 families, including c.1880A>G

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Spectrum of mutations inmutmethylmalonic acidemia and identification of a common Hispanic mutation and haplotype

Cited by 114 publications

References 32 publications

Propionyl-CoA and adenosylcobalamin metabolism in Caenorhabditis elegans: Evidence for a role of methylmalonyl-CoA epimerase in intermediary metabolism

Propionyl-CoA and adenosylcobalamin metabolism in Caenorhabditis elegans: Evidence for a role of methylmalonyl-CoA epimerase in intermediary metabolism

Mutation and haplotype analyses of the MUT gene in Japanese patients with methylmalonic acidemia

Mutation analysis and prenatal diagnosis for three families affected by isolated methylmalonic aciduria

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