Genetic disorders of vitamin B₁₂ metabolism: eight complementation groups--eight genes

Abstract

Vitamin B12 (cobalamin, Cbl) is an essential nutrient in human metabolism. Genetic diseases of vitamin B12 utilisation constitute an important fraction of inherited newborn disease. Functionally, B12 is the cofactor for methionine synthase and methylmalonyl CoA mutase. To function as a cofactor, B12 must be metabolised through a complex pathway that modifies its structure and takes it through subcellular compartments of the cell. Through the study of inherited disorders of vitamin B12 utilisation, the genes for eight complementation groups have been identified, leading to the determination of the general structure of vitamin B12 processing and providing methods for carrier testing, prenatal diagnosis and approaches to treatment.

Figure 1

Structure of vitamin B₁₂ (cobalamin). (a) The ‘R group’ corresponds to substitutions at the upper or β-axial ligand (5′-deoxyadenosyl-, methyl-, hydroxo-, cyano-). The dimethylbenzimidazole constituent (DMB) is shown coordinated to the cobalt in the lower α-axial position (‘base-on’ structure). DMB is linked to the corrin ring through a phosphoribosyl attached to a propionamide side chain. (b) Structure of methylcobalamin (MeCbl) with DMB displaced from the cobalt by a histidine residue in methionine synthase (MS; the ‘base-off/His-on’ structure). A similar configuration is observed for adenosylcobalamin (AdoCbl) bound to methylmalonyl-CoA mutase. Structures are from http://www.genome.jp using the ‘SIMCOMP Search’ utility (query C00576, vitamin B₁₂; C06410, MeCbl-MS).

Figure 2

Intracellular processing of vitamin B₁₂ showing sites of defects in complementation groups. Complementation groups are in blue and are positioned at sites of metabolic blocks (shown in red). Cobalamin intermediates are in red. Excreted metabolites due to genetic defects are in shaded boxes. Pathway details are described in the text. In the lysosome, cobalamin is released from transcobalamin (TC) through its degradation (arrow pointing to dots). In the cytosol, R groups are released by the cblC protein with the cob(II)alamin [Cob(II)] product remaining bound (dotted line emanating from the cblC protein denotes complex with cobalamin forms). The three versions of the cblD protein (cblD, cblD-1, cblD-2) illustrate the role of the protein in directing cobalamin to the mitochondrial or cytosolic pathway. In the mitochondrion, the cblB protein adds the 5′-deoxyadenosyl group, generating the active cofactor [adenosylcobalamin (AdoCbl)], which is transferred to the mut [methylmalonyl-CoA mutase (MCM)] protein. The cblA protein is proposed to act as a gatekeeper to ensure that the cofactor form that is accepted and retained by MCM is AdoCbl. In the cytosolic pathway, cob(II)alamin is bound to the cblG [methionine synthase (MS)] protein. The cblE [methionine synthase reductase (MSR)] protein catalyses generation of the active cofactor, methylcobalamin (MeCbl), or its regeneration if oxidised to cob(II)alamin during reaction cycles.

Figure 3

Mutations in the genes underlying the defects of the eight complementation groups. For each complementation group, the gene name is given in brackets. Mutations are shown as cDNA position with corresponding amino-acid change in brackets. The numbering for each is based on the cDNA sequence: +1 corresponds to the A of the ATG translation initiation codon. Nonsense and frameshift (fs) mutations are displayed above the gene whereas missense and possible splice site or cryptic splice site (ss) mutations are displayed below. Mutations are based on cblA (Refs 6, 7, 8, 9, 10), cblB (Refs 11, 12, 13), cblC (Refs 14, 15, 16, 17, 18, 19), cblD (Refs 20, 21), cblE (Refs 22, 23, 24, 25, 26), cblF (Refs 27, 28), cblG (Refs 29, 30, 31, 32) and mut (Refs 9, 13, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50).