Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria

Froese, D. Sean; Zhang, J.; Healy, Shannon; Gravel, Roy A.

doi:10.1016/j.ymgme.2009.07.014

Cited by 47 publications

(53 citation statements)

References 25 publications

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“…When compared with the absorption spectrum for base-off CNCbl ( Supplementary Fig. 1), CNCbl bound to bCblC was in the base-off state as was the case for hCblC (8). The absorption spectra of MeCbl and AdoCbl were also significantly altered by the addition of bCblC with the blue shift of the α/β-peaks at 520 and 525 nm, respectively, to 459 nm ( Fig.…”

Section: Base-off Binding Of Cncbl Mecbl and Adocblmentioning

confidence: 80%

“…The human protein hCblC, which is encoded by the defective gene in the cblC group, was characterized as a B12 trafficking chaperone involved in enzyme cofactor assimilation (7). hCblC binds cyanocobalamin (CNCbl), MeCbl and AdoCbl in the base-off states (8,9), in which the DMB ligand is dissociated from cobalt. The protein catalyzes the reductive elimination of the cyanide ligand from CNCbl (9) and the elimination of the alkyl ligands (the methyl and the 5'-deoxyadenosyl ligands of MeCbl and AdoCbl, respectively) using reduced glutathione (GSH) as the cosubstrate (10).…”

Section: Introductionmentioning

confidence: 99%

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Protection of aquo/hydroxocobalamin from reduced glutathione by a B₁₂ trafficking chaperone

Jeong

Ha²,

Kim³

2011

BMB Reports

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Section: Base-off Binding Of Cncbl Mecbl and Adocblmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Protection of aquo/hydroxocobalamin from reduced glutathione by a B₁₂ trafficking chaperone

Jeong

Ha²,

Kim³

2011

BMB Reports

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“…Froese et al demonstrated that MMACHC is naturally thermolabile (T m = 39 ° C) and that some of the most frequent mutations that occur in humans exacerbate this property [ 39 ] as well as its ability to bind Cbls [ 40 ]. Studies with the bovine isoform of MMACHC revealed that the reduced form of glutathione stabilizes MMACHC, suggesting that intracellular redox control could play a role in the regulation of the protein ' s lifetime [ 41 -44 ].…”

Section: Biophysical and Structural Characterization Of The B 12 -Promentioning

confidence: 99%

Proteomics of vitamin B12 processing

Hannibal

DiBello

Jacobsen³

2013

Clinical Chemistry and Laboratory Medicine

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The causes of cobalamin (B 12 , Cbl) deficiency are multifactorial. Whether nutritional due to poor dietary intake, or functional due to impairments in absorption or intracellular processing and trafficking events, the major symptoms of Cbl deficiency include megaloblastic anemia, neurological deterioration and in extreme cases, failure to thrive and death. The common biomarkers of Cbl deficiency (hyperhomocysteinemia and methylmalonic acidemia) are extremely valuable diagnostic indicators of the condition, but little is known about the changes that occur at the protein level. A mechanistic explanation bridging the physiological changes associated with functional B 12 deficiency with its intracellular processers and carriers is lacking. In this article, we will cover the effects of B 12 deficiency in a cblC -disrupted background (also referred to as MMACHC) as a model of functional Cbl deficiency. As will be shown, major protein changes involve the cytoskeleton, the neurological system as well as signaling and detoxification pathways. Supplementation of cultured MMACHC-mutant cells with hydroxocobalamin (HOCbl) failed to restore these variants to the normal phenotype, suggesting that a defective Cbl processing pathway produces irreversible changes at the protein level.

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“…14 High concentrations of hydroxocobalamin might stabilize the mutated cblC protein. 24,25 Betaine increases remethylation of homocysteine to methionine. 1,14 The addition of folate may also help with remethylation, but no longitudinal studies have documented this.…”

Section: Discussionmentioning

confidence: 99%

Cobalamin C Deficiency in an Adolescent With Altered Mental Status and Anorexia

Rahmandar¹,

Bawcom²,

Romano

et al. 2014

Pediatrics

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Although cobalamin (cbl) C deficiency is the most common inherited disorder of vitamin B12 metabolism, the late-onset form of the disease can be difficult to recognize because it has a broad phenotypic spectrum. In this report, we describe an adolescent female exposed to unknown illicit substances and sexual abuse who presented with psychosis, anorexia, seizures, and ataxia. The patient’s diagnosis was delayed until a metabolic workup was initiated, revealing hyperhomocysteinemia, low normal plasma methionine, and methylmalonic aciduria. Ultimately, cblC deficiency was confirmed when molecular testing showed compound heterozygosity for mutations (c.271dupA and c.482G>A) in the MMACHC gene. This diagnosis led to appropriate treatment with hydroxocobalamin, betaine, and folate, which resulted in improvement of her clinical symptoms and laboratory values. This patient demonstrates a previously unrecognized presentation of late-onset cblC deficiency. Although neuropsychiatric symptoms are common in late-onset disease, seizures and cerebellar involvement are not. Furthermore, anorexia has not been previously described in these patients. This case emphasizes that inborn errors of metabolism should be part of the differential diagnosis for a teenager presenting with altered mental status, especially when the diagnosis is challenging or neurologic symptoms are unexplained. Correct diagnosis of this condition is important because treatment is available and can result in clinical improvement.1

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Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria

Cited by 47 publications

References 25 publications

Protection of aquo/hydroxocobalamin from reduced glutathione by a B₁₂ trafficking chaperone

Protection of aquo/hydroxocobalamin from reduced glutathione by a B₁₂ trafficking chaperone

Proteomics of vitamin B12 processing

Cobalamin C Deficiency in an Adolescent With Altered Mental Status and Anorexia

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Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria

Cited by 47 publications

References 25 publications

Protection of aquo/hydroxocobalamin from reduced glutathione by a B12 trafficking chaperone

Protection of aquo/hydroxocobalamin from reduced glutathione by a B12 trafficking chaperone

Proteomics of vitamin B12 processing

Cobalamin C Deficiency in an Adolescent With Altered Mental Status and Anorexia

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Product

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Protection of aquo/hydroxocobalamin from reduced glutathione by a B₁₂ trafficking chaperone

Protection of aquo/hydroxocobalamin from reduced glutathione by a B₁₂ trafficking chaperone