A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients

Jean-Louis Guéant 1 Céline Chery 1 Abderrahim Oussalah 1 Javad Nadaf 2 David Coelho 1 Thomas Josse 1 Justine Flayac 1 Aurélie Robert 1 Isabelle Koscinski 1 Isabelle Gastin 1 Pierre Filhine-Tresarrieu 3, 1 Mihaela Pupavac 2 Alison Brebner 2 David Watkins 2 Tomi Pastinen 2 Alexandre Montpetit 2 Fadi Hariri 2 David Tregouet 4, 5 Benjamin A. Raby 6 Wendy K. Chung 7 Pierre-Emmanuel Morange 8, 9, 10 D Sean Froese 11 Matthias Baumgartner 11 Jean-François Benoist 12 Can Ficicioglu 13, 14 Virginie Marchand 15, 16 Yuri Motorin 15 Chrystele Bonnemains 1 François Feillet 1 Jacek Majewski 2 David Rosenblatt 2
Abstract : 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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Jean-Louis Guéant, Céline Chery, Abderrahim Oussalah, Javad Nadaf, David Coelho, et al.. A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients. Nature Communications, Nature Publishing Group, 2018, 9 (1), pp.67. ⟨10.1038/s41467-017-02306-5⟩. ⟨hal-01801484⟩

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