Cloning and expression of mutations demonstrating intragenic complementation in mut0 methylmalonic aciduria.

Qureshi, A; Crane, Ana M.; Matiaszuk, Nora; Rezvani, Iraj; Ledley, Fred D.; Rosenblatt, David S.

doi:10.1172/jci117166

Cited by 27 publications

(29 citation statements)

References 16 publications

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“…For example, complementation analysis of 28 cell lines with mutations of the homotetrameric enzyme argininosuccinate lyase revealed 20 cell lines that complemented between 1 and 14 of the other cell lines (30). Similarly, within 10 cell lines with deficiency of the homodimeric MMA-CoA mutase (mut0), 8 complemented 1 to 6 of the others (31). In contrast to these and other examples, our 2 cblD-variant 1 cell lines clearly complemented each of a minimum of 5 cell lines of the cblC, cblG, and cblE classes.…”

Section: Discussionmentioning

confidence: 99%

The cblD Defect Causes Either Isolated or Combined Deficiency of Methylcobalamin and Adenosylcobalamin Synthesis

Suormala

Baumgartner

Coelho

et al. 2004

Journal of Biological Chemistry

110

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Intracellular cobalamin is converted to adenosylcobalamin, coenzyme for methylmalonyl-CoA mutase and to methylcobalamin, coenzyme for methionine synthase, in an incompletely understood sequence of reactions. Genetic defects of these steps are defined as cbl complementation groups of which cblC, cblD (described in only two siblings), and cblF are associated with combined homocystinuria and methylmalonic aciduria. Here we describe three unrelated patients belonging to the cblD complementation group but with distinct biochemical phenotypes different from that described in the original cblD siblings. Two patients presented with isolated homocystinuria and reduced formation of methionine and methylcobalamin in cultured fibroblasts, defined as cblD-variant 1, and one patient with isolated methylmalonic aciduria and deficient adenosylcobalamin synthesis in fibroblasts, defined as cblD-variant 2. Cell lines from the cblD-variant 1 patients clearly complemented reference lines with the same biochemical phenotype, i.e. cblE and cblG, and the cblD-variant 2 cell line complemented cells from the mutant classes with isolated deficiency of adenosylcobalamin synthesis, i.e. cblA and cblB. Also, no pathogenic sequence changes in the coding regions of genes associated with the respective biochemical phenotypes were found. These findings indicate heterogeneity within the previously defined cblD mutant class and point to further complexity of intracellular cobalamin metabolism.

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Section: Discussionmentioning

confidence: 99%

The cblD Defect Causes Either Isolated or Combined Deficiency of Methylcobalamin and Adenosylcobalamin Synthesis

Suormala

Baumgartner

Coelho

et al. 2004

Journal of Biological Chemistry

110

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“…Detailed biochemical characterization of mutant alleles at this locus will be important because most patients are allelic compounds. Interallelic interactions between mutant subunits can occur and create an intermediate or mut-deficiency state that might otherwise be unexpected from de novo prediction algorithms [40,43]. This phenomenon makes correlations between genotype and phenotype possible for only a subset of missense alleles or when patients are homozygous.…”

Section: Methylmalonyl-coa Mutase (Mcm)mentioning

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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“…Fenton, unpubl. results, quoted by Qureshi et al, 1994) affects a residue in helix Ia7 of the barrel domain, on one of the two cy-helices that form the dimer interface. Arg 369 is salt bridged to amino acid Glu 415 provided by the other subunit.…”

Section: Mutations In the N-terminus And P/a-barrel Domain: Three Mutmentioning

confidence: 99%

Homology modeling of human methylmalonyl‐CoA mutase: A structural basis for point mutations causing methylmalonic aciduria

Thomä

Leadlay

1996

Protein Science

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Point mutations in the human gene encoding coenzymegive rise to an inherited disorder of propionic acid metabolism termed mut methylmalonic aciduria. Almost all such mutations alter amino acids in the homodimeric human enzyme that are identical to residues in the catalytic a-subunit of the heterodimeric methylmalonyl-CoA mutase from the bacterium Propianibacterium shermanii, to which the mature human enzyme shows an overall 65% sequence identity. To explore how specific mutations might cause the observed clinical phenotype, 12 known mutations were mapped onto a three-dimensional homology model of the subunit of the human enzyme, generated using the program MOD-

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Cloning and expression of mutations demonstrating intragenic complementation in mut0 methylmalonic aciduria.

Cited by 27 publications

References 16 publications

The cblD Defect Causes Either Isolated or Combined Deficiency of Methylcobalamin and Adenosylcobalamin Synthesis

The cblD Defect Causes Either Isolated or Combined Deficiency of Methylcobalamin and Adenosylcobalamin Synthesis

Genetic and genomic systems to study methylmalonic acidemia

Homology modeling of human methylmalonyl‐CoA mutase: A structural basis for point mutations causing methylmalonic aciduria

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