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

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.
Complete list of metadatas

Cited literature [41 references]  Display  Hide  Download

https://hal.univ-lorraine.fr/hal-01801484
Contributor : Julie Gonnet <>
Submitted on : Monday, May 6, 2019 - 5:03:15 PM
Last modification on : Monday, October 21, 2019 - 5:46:42 PM

File

A PRDX1 mutant allele causes a...
Publication funded by an institution

Licence


Distributed under a Creative Commons Attribution 4.0 International License

Identifiers

Citation

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⟩

Share

Metrics

Record views

341

Files downloads

77