2. Academic Validation
  3. APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients

APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients

  • Nat Commun. 2018 Jan 4;9(1):67. doi: 10.1038/s41467-017-02306-5.
Jean-Louis Guéant 1,  Céline Chéry 2,  Abderrahim Oussalah 2,  Javad Nadaf 3,  David Coelho 2,  Thomas Josse 2,  Justine Flayac 2,  Aurélie Robert 2,  Isabelle Koscinski 2,  Isabelle Gastin 2,  Pierre Filhine-Tresarrieu 2,  Mihaela Pupavac 3,  Alison Brebner 3,  David Watkins 3,  Tomi Pastinen 3,  Alexandre Montpetit 3,  Fadi Hariri 3,  David Tregouët 4,  Benjamin A Raby 5,  Wendy K Chung 6,  Pierre-Emmanuel Morange 7,  D Sean Froese 8,  Matthias R Baumgartner 8,  Jean-François Benoist 9,  Can Ficicioglu 10,  Virginie Marchand 11,  Yuri Motorin 11,  Chrystèle Bonnemains 2,  François Feillet 2,  Jacek Majewski 3,  David S Rosenblatt 3
Affiliations

Affiliations

  • 1 INSERM, UMR_S954 Nutrition-Genetics-Environmental Risk Exposure and Reference Centre of Inborn Metabolism Diseases, University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy), 54505, Nancy, France. [email protected].
  • 2 INSERM, UMR_S954 Nutrition-Genetics-Environmental Risk Exposure and Reference Centre of Inborn Metabolism Diseases, University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy), 54505, Nancy, France.
  • 3 Department of Human Genetics, McGill University and Research Institute McGill University Health Centre, Montreal, H4A 3J1, Quebec, Canada.
  • 4 Sorbonne Universités, UPMC University Paris 06, Institut National pour la Santé et la Recherche Médicale (INSERM), ICAN Institute for Cardiometabolism and Nutrition, Unité Mixte de Recherche en Santé (UMR_S) 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, 75013 Paris, France.
  • 5 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, United States of America.
  • 6 Departments of Pediatrics and Medicine, Columbia University, New York, NY, 10032, United States of America.
  • 7 INSERM, UMR_S1062, Nutrition Obesity and Risk of Thrombosis, Aix-Marseille University, 13005, Marseille, France.
  • 8 Division of Metabolism and Children's Research Centre (CRC), University Children's Hospital, CH-8032, Zürich, Switzerland.
  • 9 Service de Biochimie Hormonologie, Hôpital Robert Debré, 75019, Paris, France.
  • 10 Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, United States of America.
  • 11 Laboratoire Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), UMR7365 CNRS - Université de Lorraine and FR3209 CNRS- Université de Lorraine, 54505, Nancy, France.
PMID: 29302025 DOI: 10.1038/s41467-017-02306-5
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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