Novel Deletion Mutation Identified in a Patient with Late-Onset Combined Methylmalonic Acidemia and Homocystinuria, cblC Type
Combined methylmalonic aciduria and homocystinuria, cblC type (MMACHC), is the most common inborn error of cellular vitamin B12 metabolism and is caused by mutations in the MMACHC gene. This metabolic disease results in impaired intracellular synthesis of adenosylcobalamin and methylcobalamin, coenzymes for the methylmalonyl-CoA mutase and methionine synthase enzymes, respectively. The inability to produce normal levels of these two coenzymes leads to increased concentrations of methylmalonic acid and homocysteine in plasma and urine, together with normal or decreased concentration of methionine in plasma. Here, we report a novel homozygous deletion mutation (NM_015506.2:c.392_394del) resulting in an in-frame deletion of amino acid Gln131 and late-onset disease in a 23-year-old male. The patient presented with sensory and motoric disabilities, urine and fecal incontinence, and light cognitive impairment. There was an excessive urinary excretion of methylmalonic acid and greatly elevated plasma homocysteine. The clinical symptoms and the laboratory abnormalities responded partly to treatment with hydroxycobalamin, folinic acid, methionine, and betaine. Studies on patient fibroblasts together with spectroscopic activity assays on recombinant MMACHC protein reveal that Gln131 is crucial in order to maintain enzyme activity. Furthermore, structural analyses show that Gln131 is one of only two residues making hydrogen bonds to the tail of cobalamin. Circular dichroism spectroscopy indicates that the 3D structure of the deletion mutant is folded but perturbed compared to the wild-type protein.
KeywordsSodium Dithionite Methylmalonic Acid Patient Fibroblast Methylmalonic Acidemia Methylcitric Acid
This work was supported by grants from University of Oslo and the Norwegian Research Council of Norway and the South-East Health Authority of Norway. B.F. was supported by a grant from Swiss National Science Foundation (320000_122568 and 31003A_138521). P.H.B. also received grants from “Legatet til Henrik Homans Minde” and “Dr. Fürst medisinske laboratoriums fond til klinisk kjemisk og klinisk fysiologisk forskning”.
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