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

Jean-Louis Guéant (), Céline Chéry, Abderrahim Oussalah, Javad Nadaf, David Coelho, Thomas Josse, Justine Flayac, Aurélie Robert, Isabelle Koscinski, Isabelle Gastin, Pierre Filhine-Tresarrieu, Mihaela Pupavac, Alison Brebner, David Watkins, Tomi Pastinen, Alexandre Montpetit, Fadi Hariri, David Tregouët, Benjamin A Raby, Wendy K. Chung, Pierre-Emmanuel Morange, D. Sean Froese, Matthias R. Baumgartner, Jean-François Benoist, Can Ficicioglu, Virginie Marchand, Yuri Motorin, Chrystèle Bonnemains, François Feillet, Jacek Majewski and David S. Rosenblatt
Additional contact information
Jean-Louis Guéant: University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Céline Chéry: University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Abderrahim Oussalah: University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Javad Nadaf: McGill University and Research Institute McGill University Health Centre
David Coelho: University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Thomas Josse: University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Justine Flayac: University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Aurélie Robert: University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Isabelle Koscinski: University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Isabelle Gastin: University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Pierre Filhine-Tresarrieu: University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Mihaela Pupavac: McGill University and Research Institute McGill University Health Centre
Alison Brebner: McGill University and Research Institute McGill University Health Centre
David Watkins: McGill University and Research Institute McGill University Health Centre
Tomi Pastinen: McGill University and Research Institute McGill University Health Centre
Alexandre Montpetit: McGill University and Research Institute McGill University Health Centre
Fadi Hariri: McGill University and Research Institute McGill University Health Centre
David Tregouët: Team Genomics & Pathophysiology of Cardiovascular Diseases
Benjamin A Raby: Harvard Medical School
Wendy K. Chung: Columbia University
Pierre-Emmanuel Morange: INSERM, UMR_S1062, Nutrition Obesity and Risk of Thrombosis, Aix-Marseille University
D. Sean Froese: University Children’s Hospital
Matthias R. Baumgartner: University Children’s Hospital
Jean-François Benoist: Hôpital Robert Debré
Can Ficicioglu: Perelman School of Medicine at the University of Pennsylvania
Virginie Marchand: UMR7365 CNRS - Université de Lorraine and FR3209 CNRS- Université de Lorraine
Yuri Motorin: UMR7365 CNRS - Université de Lorraine and FR3209 CNRS- Université de Lorraine
Chrystèle Bonnemains: University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
François Feillet: University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Jacek Majewski: McGill University and Research Institute McGill University Health Centre
David S. Rosenblatt: McGill University and Research Institute McGill University Health Centre

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-017-02306-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02306-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-017-02306-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().