Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type

Lerner‐Ellis, Jordan; Tirone, Jamie C.; Pawelek, Peter D.; Doré, Carole; Atkinson, Janet L; Watkins, David; Morel, Chantal F.; Fujiwara, Takuya; Moras, Emily; Hosack, Angela; Dunbar, Gail V; Antonická, Hana; Forgetta, Vincenzo; Dobson, C M; Leclerc, Daniel; Gravel, Roy A.; Shoubridge, Eric A.; Coulton, James W.; Lepage, Pierre; Rommens, Johanna M.; Morgan, Kenneth; Rosenblatt, David S.

doi:10.1038/ng1683

Cited by 336 publications

(342 citation statements)

References 23 publications

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“…The nonsense c.608G>A (p.W203X) mutation found in our case has been previously described in patients of Hispanic origin with early-onset form of CblC (Lerner-Ellis et al 2005Weisfeld-Adams et al 2010). A similar nonsense mutation, c.609G>A, is the most common mutation in patients of Chinese descent.…”

Section: Discussionsupporting

confidence: 74%

“…While more than 50 mutations have been described, three common mutations exist, which demonstrate genotype-specific age of onset. The c.271dupA and c.331C>T mutations are associated with early-onset disease, while the c.394C>T mutation typically leads to lateonset disease (Lerner-Ellis et al 2005). Genotypic differences in age of onset are likely due to mRNA stability and transcript levels.…”

Section: Discussionmentioning

confidence: 99%

“…The missense c.482G>A mutation is reported to be a late-onset mutation, with patients generally presenting in second or third decade (Lerner-Ellis et al 2005Morel et al 2006;Thauvin-Robinet et al 2007). A case series of five patients identified through NBS with homozygous c.482G>A mutations demonstrated that all were clinically well at age 2.5 months (Lin et al 2009).…”

Section: Discussionmentioning

confidence: 99%

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Cobalamin C Disease Missed by Newborn Screening in a Patient with Low Carnitine Level

et al. 2015

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Cobalamin C (CblC) disease is the most common inherited disorder of intracellular cobalamin metabolism. It is a multisystemic disorder mainly affecting the eye and brain and characterized biochemically by methylmalonic aciduria, low methionine level, and homocystinuria. We report a patient found to have CblC disease who initially presented with low carnitine and normal propionylcarnitine (C3) levels on newborn screen. Newborn screening likely failed to detect CblC in this patient because of both his low carnitine level and the presence of a mild phenotype.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Cobalamin C Disease Missed by Newborn Screening in a Patient with Low Carnitine Level

et al. 2015

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“…26). Deficiency in cblF results in defective lysosomal Cbl transport (27), and the cblC gene was recently shown to be a homologue of TonB, a bacterial protein involved in Cbl transport (28). We have now demonstrated an aqCbl reductase function for MSR.…”

Section: Discussionmentioning

confidence: 81%

Human methionine synthase reductase is a molecular chaperone for human methionine synthase

Yamada

Gravel

Toraya

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Sustained activity of mammalian methionine synthase (MS) requires MS reductase (MSR), but there have been few studies of the interactions between these two proteins. In this study, recombinant human MS (hMS) and MSR (hMSR) were expressed in baculovirus-infected insect cells and purified to homogeneity. hMSR maintained hMS activity at a 1:1 stoichiometric ratio with a K act value of 71 nM. Escherichia coli MS, however, was not activated by hMSR. Moreover, hMS was not significantly active in the presence of E. coli flavodoxin and flavodoxin reductase, which maintain the activity of E. coli MS. These results indicate that recognition of MS by their reductive partners is very strict, despite the high homology between MS from different species. The effects of hMSR on the formation of hMS holoenzyme also were examined by using crude extracts of baculovirus-infected insect cells containing hMS apoenzyme (apoMS). In the presence of MSR and NADPH, holoenzyme formation from apoMS and methylcobalamin was significantly enhanced. The observed stimulation is shown to be due to stabilization of human apoMS in the presence of MSR. Apoenzyme alone is quite unstable at 37°C. MSR also is able to reduce aquacobalamin to cob(II)alamin in the presence of NADPH, and this reduction leads to stimulation of the conversion of apoMS and aquacobalamin to MS holoenzyme. Based on these findings, we propose that MSR serves as a special chaperone for hMS and as an aquacobalamin reductase, rather than acting solely in the reductive activation of MS.aquacobalamin reductase ͉ cobalamin ͉ holoenzyme formation

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“…V itamin B 12 (or cyanocobalamin, CNCbl) was discovered exactly 60 years ago in the laboratories of Folkers and Smith as the anti-pernicious anemia factor (1, 2), and its structure was revealed a few years later by the crystallographic studies in the Hodgkin laboratory (3). B 12 is one of the most complex cofactors in nature and belongs to the family of tetrapyrrolic-derived macrocyclic compounds.…”

mentioning

confidence: 99%

Decyanation of vitamin B ₁₂ by a trafficking chaperone

Kim

Gherasim

Banerjee

2008

Proc. Natl. Acad. Sci. U.S.A.

194

168

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The mystery of how the cyanide group in vitamin B12 or cyanocobalamin, discovered 60 years ago, is removed, has been solved by the demonstration that the trafficking chaperone, MMACHC, catalyzes a reductive decyanation reaction. Electrons transferred from NADPH via cytosolic flavoprotein oxidoreductases are used to cleave the cobalt-carbon bond with reductive elimination of the cyanide ligand. The product, cob(II)alamin, is a known substrate for assimilation into the active cofactor forms, methylcobalamin and 5 -deoxyadenosylcobalamin, and is bound in the ''base-off'' state that is needed by the two B12-dependent target enzymes, methionine synthase and methylmalonyl-CoA mutase. Defects in MMACHC represent the most common cause of inborn errors of B12 metabolism, and our results explain the observation that fibroblasts from these patients are poorly responsive to vitamin B12 but show some metabolic correction with aquocobalamin, a cofactor form lacking the cyanide ligand, which is mirrored by patients showing poorer clinical responsiveness to cyano-versus aquocobalamin.cobalamin ͉ flavin oxidoreductase ͉ methylmalonic aciduria ͉ homocystinuria ͉ cyanide V itamin B 12 (or cyanocobalamin, CNCbl) was discovered exactly 60 years ago in the laboratories of Folkers and Smith as the anti-pernicious anemia factor (1, 2), and its structure was revealed a few years later by the crystallographic studies in the Hodgkin laboratory (3). B 12 is one of the most complex cofactors in nature and belongs to the family of tetrapyrrolic-derived macrocyclic compounds. Five of the six ligands to the central cobalt atom in free B 12 are endogenous, being provided by the corin ring itself (Fig. 1A). In CNCbl, the sixth ligand, which occupies the upper axial position, is a cyano group. Although the biological origin of the cyano group in vitamin B 12 is unknown, it is the cofactor form commonly used in multivitamin formulations and one that individuals on vitamin supplementation are regularly exposed to. Decyanation of CNCbl is a prerequisite for its conversion to the active cofactor forms used by mammals in which the cyano ligand is replaced by a methyl group (in methylcobalamin) or a 5Ј-deoxyadenosyl group (in coenzyme B 12 or 5Ј-deoxyadenosylcobalamin) (Fig. 1B).Defects in B 12 metabolism are inherited as autosomal recessive disorders and are classified as belonging to one of eight genetic complementation groups, cblA-G and mut (4). Two loci, cblG and mut, encode B 12 -dependent enzymes: methionine synthase, which is cytoplasmic, and methylmalonyl-CoA mutase, which is mitochondrial. The remaining loci encode functions needed for intercompartmental trafficking and assimilation of the cofactor into its active forms. B 12 is present at relatively low concentrations in human tissues (5) and is reactive in all three of its biologically relevant oxidation states, factors that pose challenges for its unescorted delivery to target enzymes (6). The problem is further exacerbated by the use of the ''base-off/Hison'' conformation of the cofactor ...

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Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type

Cited by 336 publications

References 23 publications

Cobalamin C Disease Missed by Newborn Screening in a Patient with Low Carnitine Level

Cobalamin C Disease Missed by Newborn Screening in a Patient with Low Carnitine Level

Human methionine synthase reductase is a molecular chaperone for human methionine synthase

Decyanation of vitamin B ₁₂ by a trafficking chaperone

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Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type

Cited by 336 publications

References 23 publications

Cobalamin C Disease Missed by Newborn Screening in a Patient with Low Carnitine Level

Cobalamin C Disease Missed by Newborn Screening in a Patient with Low Carnitine Level

Human methionine synthase reductase is a molecular chaperone for human methionine synthase

Decyanation of vitamin B 12 by a trafficking chaperone

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Decyanation of vitamin B ₁₂ by a trafficking chaperone