Subcellular location of MMACHC and MMADHC, two human proteins central to intracellular vitamin B(12) metabolism.

[homocystinuria without methylmalonic aciduria]

MMACHC and MMADHC are the genes responsible for cblC and cblD defects of vitamin B (12 ) metabolism , respectively . Patients with cblC and cblD defects present with various combinations of methylmalonic aciduria (MMA ) and homocystinuria (HC ). Those with cblC mutations have both MMA and HC whereas cblD patients can present with one of three distinct biochemical phenotypes : isolated MMA , isolated HC , or combined MMA and HC . Based on the subcellular localization of these enzymatic pathways it is thought that MMACHC functions in the cytoplasm while MMADHC functions downstream of MMACHC in both the cytoplasm and the mitochondrion . In this study we determined the subcellular location of MMACHC and MMADHC by immunofluorescence and subcellular fractionation . We show that MMACHC is cytoplasmic while MMADHC is both mitochondrial and cytoplasmic , consistent with the proposal that MMADHC acts as a branch point for vitamin B (12 ) delivery to the cytoplasm and mitochondria . The factors that determine the distribution of MMADHC between the cytoplasm and mitochondria remain unknown . Functional complementation experiments showed that retroviral expression of the GFP tagged constructs rescued all biochemical defects in cblC and cblD fibroblasts except propionate incorporation in cblD-MMA cells , suggesting that the endogenous mutant protein interferes with the function of the transduced wild type construct .

Diseases
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Diseases presenting "cbld defects" symptom

homocystinuria without methylmalonic aciduria

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