Role of the genomic and epigenomic alterations in the molecular mechanisms at the origin of the pathologies associated with rare inborn errors of vitamin B12 metabolism

Genetic defects of vitamin B12 or cobalamin (cbl) metabolism lead to a decrease of methionine synthase activity that could result in a decrease of S-adenosyl methionine (SAM) synthesis and in the methylation index SAM / SAH that could be responsible for methylation alterations of various substrates. Patients with inherited disorders of cbl metabolism generally have a wide spectrum of pathologies suggesting that various cellular processes may be affected. However, the molecular mechanisms responsible for the development of these disorders are not well known. In order to better understand these mechanisms, we have used fibroblasts of patients with cblC and cblG genetic defects to characterize the modifications of their transcriptome, methylome and proteome. Our data show a modification in the expression of many genes involved in developmental, neurological, ophthalmologic and cardiovascular processes. These associations are consistent with the clinical presentation of the patients. We have also provided evidence of abnormal splicing of genes important for cytoskeleton organization, stress response, methylation and RNA binding. The study of differentially expressed or spliced genes has allowed us to identify various RNA binding proteins (RBP) such as HuR and HNRNPL that are involved in these modifications. The study of DNA methylation also revealed modifications in genes playing a role in developmental and neurological pathologies. No variation in methylation of histones or mRNA has been detected. The proteome study has confirmed that alternative splicing was affected and has suggested that mitochondrial metabolism was also altered. Our results contribute to a better understanding of the molecular mechanisms at the origin of the pathologies associated with the cblC and cblG defects and highlight the crucial role of RBP in these processes.