APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.
Fiche publication
Date publication
janvier 2018
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GUEANT Jean-Louis, Dr MARCHAND Virginie, Dr OUSSALAH Abderrahim
Tous les auteurs :
Guéant JL, Chéry C, Oussalah A, Nadaf J, Coelho D, Josse T, Flayac J, Robert A, Koscinski I, Gastin I, Filhine-Tresarrieu P, Pupavac M, Brebner A, Watkins D, Pastinen T, Montpetit A, Hariri F, Tregouët D, Raby BA, Chung WK, Morange PE, Froese DS, Baumgartner MR, Benoist JF, Ficicioglu C, Marchand V, Motorin Y, Bonnemains C, Feillet F, Majewski J, Rosenblatt DS
Lien Pubmed
Résumé
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 B 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.
Mots clés
Alleles, Azacitidine, pharmacology, Base Sequence, Carrier Proteins, genetics, Enzyme Inhibitors, pharmacology, Epistasis, Genetic, Family Health, Female, Fibroblasts, drug effects, Heterozygote, Humans, Male, Metabolism, Inborn Errors, genetics, Mutation, Pedigree, Peroxiredoxins, genetics, Vitamin B 12, metabolism, Whole Genome Sequencing
Référence
Nat Commun. 2018 01 4;9(1):67