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APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.

Jean-Louis GuéantCéline ChéryAbderrahim OussalahJavad NadafDavid CoelhoThomas JosseJustine FlayacAurélie RobertIsabelle KoscinskiIsabelle GastinPierre Filhine-TresarrieuMihaela PupavacAlison BrebnerDavid WatkinsTomi PastinenAlexandre MontpetitFadi HaririDavid TregouëtBenjamin A RabyWendy K ChungPierre-Emmanuel MorangeD Sean FroeseMatthias R BaumgartnerJean-François BenoistCan FiciciogluVirginie MarchandYuri MotorinChrystèle BonnemainsFrançois FeilletJacek MajewskiDavid S Rosenblatt
Published in: Nature communications (2018)
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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