The cblC group of defect of remethylation (RM) of methionine is the most frequent inherited error of methionine metabolism. It is due to mutations in MMACHC gene involved in the intracellular transport of vitamin B12 and produces severe and sometimes fatal decompensations in the few weeks after birth and megaloblastic anemia and neurological abnormalities. Recently, we discovered a new type of cblC that we named epi-cblC in 7 patients from Europe and the United States (Guéant et al, Nature Communications, 2018). Using DNA methylome profiling, we identified a MMACHC epimutation that was present in 3 generation and in the sperm of the case’s fathers. MMACHC belongs to a gene trio in which it is flanked by CCDC163P and PRDX1 in the opposite orientation (trio reverse(R1)/forward(F2)/reverse(R3)). We found a mutation in PRDX1 that produced an antisense transcription encompassing the CCDC163P/MMACHC promoter, resulting in an H3K36me3 mark and the generation of the epimutation. To our knowledge, this is the first example of an epimutation that is maintained in sperm and transmitted in 3 generations in inherited errors of metabolism. It is also the first example of an epimutation involved in a trio of genes. The core hypothesis of the project is that epimutations in trios of genes may contribute to the causes and consequences of inborn errors of metabolism and define a new type of inborn errors that could be transmitted through generations in patients with either unknown genetic causes or heterozygous mutations despite typical metabolic and clinical manifestations. The project will search for epimutations in such patients with inherited errors of metabolism and will study the mechanisms that explain the stability and transgenerational transmission of the epimutation. It will be focused on RM disorders and will search also epimutations in gene trios related to other metabolic rare diseases. By describing epimutations in diseases related to gene trios, we expect to define a new type of inborn errors and to elucidate the mechanisms that underlie the maintenance of epimutations in sperm and their transmission through generations. We expect also to improve the management of epi-cblC cases by innovative therapies that target either the aberrant transcription or DNMTs and SETD2.
Coordinator of project: Jean-Louis Guéant
Inserm UMRS 1256, Nutrition-Génétique-Exposition aux risques environnementaux, Faculté de Médecine - BP 184, 54511 Vandoeuvre les Nancy, France. The duration cannot exceed 24 months.
The target start date for the position is November-December 2019, with some flexibility on the exact start date.
Applicants are requested to submit the following materials:
• A cover letter applying for the position
• Full CV and list of publications
• Academic transcripts (unofficial versions are fine)
Deadline for application is August 15th. Applicants will be interviewed by an Ad Hoc Commission by August 30th.
Applications are only accepted through email. All document must be sent to
Inserm UMRS 1256, Nutrition-Génétique-Exposition aux risques environnementaux, Faculté de Médecine - BP 184, 54511 Vandoeuvre les Nancy, Lorraine, France
|Title||Post-doctoral position proposal: EpiGenOmics/genomic/metabolic interplay in pathomechanisms of iNborn Errors of methionine metabolism|
|Employer||Lorraine Université d'Excellence (LUE)|
|Job location||34 Cours Léopold, 54000 Nancy|
|Published||May 27, 2019|
|Application deadline||August 15, 2019|
|Job types||Postdoc  |
|Fields||Clinical Sciences,   Pathology,   Genetics,   Cell Biology  |