Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product.
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ABSTRACT:
SUBMITTER: Hannibal L
PROVIDER: S-EPMC2709701 | biostudies-literature | 2009 Aug
REPOSITORIES: biostudies-literature
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Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product.
Hannibal Luciana L Kim Jihoe J Brasch Nicola E NE Wang Sihe S Rosenblatt David S DS Banerjee Ruma R Jacobsen Donald W DW
Molecular genetics and metabolism 20090416 4
The MMACHC gene product of the cblC complementation group, referred to as the cblC protein, catalyzes the in vitro and in vivo decyanation of cyanocobalamin (vitamin B(12)). We hypothesized that the cblC protein would also catalyze the dealkylation of newly internalized methylcobalamin (MeCbl) and 5'-deoxyadenosylcobalamin (AdoCbl), the naturally occurring alkylcobalamins that are present in the diet. The hypothesis was tested in cultured endothelial cells using [(57)Co]-AdoCbl and MeCbl analogs ...[more]
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Project description:To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B12 metabolism that we name "epi-cblC". The subjects are compound heterozygotes for a genetic mutation and for a promoter epimutation, detected in blood, fibroblasts, and sperm, at the MMACHC locus; 5-azacytidine restores the expression of MMACHC in fibroblasts. MMACHC is flanked by CCDC163P and PRDX1, which are in the opposite orientation. The epimutation is present in three generations and results from PRDX1 mutations that force antisense transcription of MMACHC thereby possibly generating a H3K36me3 mark. The silencing of PRDX1 transcription leads to partial hypomethylation of the epiallele and restores the expression of MMACHC. This example of epi-cblC demonstrates the need to search for compound epigenetic-genetic heterozygosity in patients with typical disease manifestation and genetic heterozygosity in disease-causing genes located in other gene trios.
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