Novel inborn error of vitamin B12 metabolism caused by mutations in «ABCD4»

Vitamin B12 (cobalamin, Cbl) is an essential cofactor for two human enzymes: methylmalonyl-CoA mutase (MUT) and methionine synthase (MTR). MUT utilizes 5'-deoxyadenosylcobalamin (AdoCbl) to convert methylmalonyl-CoA to succinyl-CoA in the mitochondria, whereas MTR utilizes methylcobalamin (MeCbl) to convert homocysteine to methionine in the cytoplasm. To date, eight complementation groups (cblA-G and mut), each the result of mutations at a different gene, have been discovered to be involved in the intracellular metabolism of cobalamin. A patient presented at birth, following an abnormal newborn screen, with hypotonia, lethargy, poor feeding and bone marrow suppression. There were elevated levels of methylmalonic acid and homocysteine, suggestive of a defect in vitamin B12 metabolism. Studies of cultured fibroblast showed decreased function of the cobalamin-dependent enzymes, MTR and MUT. There was increased uptake of labelled cyanocobalamin (CNCbl) but decreased synthesis of the cobalamin cofactors MeCbl and AdoCbl, with accumulation of "free" (i.e. non-protein bound) CNCbl in the cells. The cellular phenotype mimicked that of the cblF disorder caused by mutations in the LMBRD1 gene encoding the lysosomal membrane protein LMBD1 that is thought to play a role in transfer of cobalamin across the lysosomal membrane into the cytoplasm. However, cells from the patient complemented those from all known complementation groups, including cblF, and no mutations in LMBRD1 were found. Whole-exome sequencing led to the identification of two mutations in the ABCD4 gene: c.956A>G (p.Y319C) and c.1746_1747insCT (p.E583LfsX9). Two additional patients with deleterious ABCD4 mutations were later found. Transfection of patient fibroblasts with wild type ABCD4 led to rescue of all abnormal cellular phenotypes. This thesis reports that this novel disorder, named cblJ, is an autosomal recessive disorder caused by mutations in ABCD4. The findings suggest that ABCD4, an ABC half-transporter, is another essential component of intracellular cobalamin metabolism.

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