Genetic disorders of vitamin B<sub>12</sub>metabolism: eight complementation groups – eight genes

Froese, D. Sean; Gravel, Roy A.

doi:10.1017/s1462399410001651

Cited by 115 publications

(90 citation statements)

References 152 publications

(200 reference statements)

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“…The human G-protein chaperone, MMAA (methylmalonic aciduria type A protein, mitochondrial; gene product of cblA), is involved in the assembly of adenosylcobalamin (AdoCbl, coenzyme B 12 )-dependent methylmalonyl-CoA mutase (MCM) (5,6). Mutations in MMAA and MCM result in methylmalonic aciduria, a genetically inherited metabolic disease that is devastating in newborns and infants (7). Bacterial homologs of MMAA are involved in assembly of other metalloproteins and include HypB for hydrogenase (8) and UreG for urease (9).…”

mentioning

confidence: 99%

Visualization of a radical B ₁₂ enzyme with its G-protein chaperone

Jost¹,

Cracan

Hubbard³

et al. 2015

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

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G-protein metallochaperones ensure fidelity during cofactor assembly for a variety of metalloproteins, including adenosylcobalamin (AdoCbl)-dependent methylmalonyl-CoA mutase and hydrogenase, and thus have both medical and biofuel development applications. Here, we present crystal structures of IcmF, a natural fusion protein of AdoCbl-dependent isobutyryl-CoA mutase and its corresponding G-protein chaperone, which reveal the molecular architecture of a G-protein metallochaperone in complex with its target protein.These structures show that conserved G-protein elements become ordered upon target protein association, creating the molecular pathways that both sense and report on the cofactor loading state. Structures determined of both apo-and holo-forms of IcmF depict both open and closed enzyme states, in which the cofactor-binding domain is alternatively positioned for cofactor loading and for catalysis. Notably, the G protein moves as a unit with the cofactorbinding domain, providing a visualization of how a chaperone assists in the sequestering of a precious cofactor inside an enzyme active site.

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mentioning

confidence: 99%

Visualization of a radical B ₁₂ enzyme with its G-protein chaperone

Jost¹,

Cracan

Hubbard³

et al. 2015

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

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“…In fact, a recent review on digenic inheritance cautions medical geneticists to consider digenic inheritance as a possible mechanism for patients with novel phenotypes (Schaffer 2013). Further, the clinical features observed among patients with LMBRD1 are widely variable (Froese and Gravel 2010;Watkins and Rosenblatt 2011), and specifically patients with the c.1056delG alteration in the compound heterozygous or homozygous state show considerable phenotypic variability ranging from death in infancy to asymptomatic long-term survival (Rutsch et al 2009). The unaffected mother, unaffected father, and unaffected sister do not carry both the MTR and LMBRD1 alterations which would have ruled out the possibility for a digenic affect.…”

Section: Discussionmentioning

confidence: 99%

“…Autosomal recessive mutations within at least 19 genes are associated with disorders of cobalamin metabolism. To our knowledge, there have been no reports of digenic inheritance (Sarafoglou and Hoffman 2009;Froese and Gravel 2010).…”

Section: Introductionmentioning

confidence: 98%

“…Clinical symptoms generally include hematologic and neurologic defects . However, even within a single complementation class clinical symptoms and biochemical profile can be highly variable, which led to the need to distinguish the disorders based on the affected gene (Froese and Gravel 2010). Autosomal recessive mutations within at least 19 genes are associated with disorders of cobalamin metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Diagnostic Exome Sequencing and Tailored Bioinformatics of the Parents of a Deceased Child with Cobalamin Deficiency Suggests Digenic Inheritance of the MTR and LMBRD1 Genes

González

et al. 2014

JIMD Reports

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Disorders of cobalamin deficiency are a heterogeneous group of disorders with at least 19 autosomal recessive-associated genes. Familial samples of an infant who died due to presumed cobalamin deficiency were referred for clinical exome sequencing. The patient died before obtaining a blood sample or skin biopsy, autopsy was declined, and DNA yielded from the newborn screening blood spot was insufficient for diagnostic testing. Whole-exome sequencing of the mother, father, and unaffected sister and tailored bioinformatics analysis was applied to search for mutations in underlying disorders with recessive inheritance. This approach identified alterations within two genes, each of which was carried by one parent. The mother carried a missense alteration in the MTR gene (c.3518C>T; p.P1173L) which was absent in the father and the sister. The father carried a translational frameshift alteration in the LMBRD1 gene (c.1056delG; p.L352Lfs*18) which was absent in the mother and present in the heterozygous state in the sister. These mutations in the MTR (MIM# 156570) and LMBRD1 (MIM# 612625) genes have been described in patients with disorders of cobalamin metabolism complementation groups cblG and cblF, respectively. The child's clinical presentation and biochemical results demonstrated overlap with both cblG and cblF. Sanger sequencing using DNA from the infant's blood spot confirmed the inheritance of the two alterations in compound heterozygous form. We present the first example of exome sequencing leading to a diagnosis in the absence of the affected patient. Furthermore, the data support the possibility for potential digenic inheritance associated with cobalamin deficiency.

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“…Adenosylcobalamin (AdoCbl) is required for activity of mitochondrial enzyme methylmalonyl CoA mutase (MUT) which converts methylmalonyl-CoA to succinyl-CoA, and methylcobalamin (MeCbl) is required for activity of cytoplasmic enzyme methionine synthase (MS) that catalyzes methylation of homocysteine to form methionine (Froese and Gravel 2010;Watkins and Rosenblatt 2011). Deficiency in cobalamin or impaired absorption of cobalamin can result in accumulation of methylmalonic acid and homocysteine in blood and serum homocysteine and urine homocystine.…”

Section: Introductionmentioning

confidence: 99%

Defect of Cobalamin Intracellular Metabolism Presenting as Diabetic Ketoacidosis: A Rare Manifestation

et al. 2013

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Hypoglycemia is the usual feature of commonly occurring organic acidemias. Organic acidemias manifesting as hyperglycemia or diabetic ketoacidosis are rare and only a few cases have been reported. We report a 13-monthold boy who presented with vomiting, dehydration, coma, hyperglycemia, high anion gap metabolic acidosis and ketosis, mimicking diabetic ketoacidosis (DKA). Treatment with parenteral fluid, electrolytes, and insulin infusion resulted in an improvement in hyperglycemia, but persistence of metabolic acidosis and lack of improvement of neurologic status led us to suspect an organic acidemia. Urinary organic acid analysis revealed increased methylmalonic acid levels. In addition, hyperhomocysteinemia and homocystinuria were also noted in presence of normal vitamin B 12 levels. This confirmed the diagnosis of cobalamin metabolism defect leading to combined methylmalonic aciduria and homocystinuria. There was some improvement in neurologic status and metabolic parameters after treatment with low-protein diet, vitamin B 12 , folic acid, and L-carnitine, but he ultimately succumbed to polymicrobial nosocomial sepsis. The entire MMACHC gene of the patient was sequenced and no mutations were identified. This is probably the first case report of cobalamin intracellular metabolism defect (CblC/CblD/ CblF/CblJ or ABCD4) presenting as diabetic ketoacidosis.

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Genetic disorders of vitamin B₁₂metabolism: eight complementation groups – eight genes

Cited by 115 publications

References 152 publications

Visualization of a radical B ₁₂ enzyme with its G-protein chaperone

Visualization of a radical B ₁₂ enzyme with its G-protein chaperone

Diagnostic Exome Sequencing and Tailored Bioinformatics of the Parents of a Deceased Child with Cobalamin Deficiency Suggests Digenic Inheritance of the MTR and LMBRD1 Genes

Defect of Cobalamin Intracellular Metabolism Presenting as Diabetic Ketoacidosis: A Rare Manifestation

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Genetic disorders of vitamin B12metabolism: eight complementation groups – eight genes

Cited by 115 publications

References 152 publications

Visualization of a radical B 12 enzyme with its G-protein chaperone

Visualization of a radical B 12 enzyme with its G-protein chaperone

Diagnostic Exome Sequencing and Tailored Bioinformatics of the Parents of a Deceased Child with Cobalamin Deficiency Suggests Digenic Inheritance of the MTR and LMBRD1 Genes

Defect of Cobalamin Intracellular Metabolism Presenting as Diabetic Ketoacidosis: A Rare Manifestation

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Genetic disorders of vitamin B₁₂metabolism: eight complementation groups – eight genes

Visualization of a radical B ₁₂ enzyme with its G-protein chaperone

Visualization of a radical B ₁₂ enzyme with its G-protein chaperone