{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:42:40Z","timestamp":1790786560556,"version":"4.1.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2020,2,18]],"date-time":"2020-02-18T00:00:00Z","timestamp":1581984000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Foundation J\u00e9r\u00f4me Lejeune"},{"name":"CHRU Nancy Hospital and R\u00e9gion Lorraine"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,29]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Vitamin B12 or cobalamin (Cbl) metabolism can be affected by genetic defects leading to defective activity of either methylmalonyl-CoA mutase or methionine synthase or both enzymes. Patients usually present with a wide spectrum of pathologies suggesting that various cellular processes could be affected by modifications in gene expression. We have previously demonstrated that these genetic defects are associated with subcellular mislocalization of RNA-binding proteins (RBP) and subsequent altered nucleo-cytoplasmic shuttling of mRNAs. In order to characterize the possible changes of gene expression in these diseases, we have investigated global gene expression in fibroblasts from patients with cblC and cblG inherited disorders by RNA-seq. The most differentially expressed genes are strongly associated with developmental processes, neurological, ophthalmologic and cardiovascular diseases. These associations are consistent with the clinical presentation of cblC and cblG disorders. Multivariate analysis of transcript processing revaled splicing alterations that led to dramatic changes in cytoskeleton organization, response to stress, methylation of macromolecules and RNA binding. The RNA motifs associated with this differential splicing reflected a potential role of RBP such as HuR and HNRNPL. Proteomic analysis confirmed that mRNA processing was significantly disturbed. This study reports a dramatic alteration of gene expression in fibroblasts of patients with cblC and cblG disorders, which resulted partly from disturbed function of RBP. These data suggest to evaluate the rescue of the mislocalization of RBP as a potential strategy in the treatment of severe cases who are resistant to classical treatments with co-enzyme supplements.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa027","type":"journal-article","created":{"date-parts":[[2020,2,13]],"date-time":"2020-02-13T20:10:37Z","timestamp":1581624637000},"page":"1969-1985","source":"Crossref","is-referenced-by-count":12,"title":["Analysis of fibroblasts from patients with cblC and cblG genetic defects of cobalamin metabolism reveals global dysregulation of alternative splicing"],"prefix":"10.1093","volume":"29","author":[{"given":"Charif","family":"Rashka","sequence":"first","affiliation":[{"name":"Inserm UMRS 1256 NGERE \u2013 Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, 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R","family":"Baumgartner","sequence":"additional","affiliation":[{"name":"Radiz \u2013 Rare Disease Initiative Z\u00fcrich, Clinical Research Priority Program for Rare Diseases, University of Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S","family":"Rosenblatt","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Feillet","sequence":"additional","affiliation":[{"name":"Inserm UMRS 1256 NGERE \u2013 Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, France"},{"name":"National Center of Inborn Errors of Metabolism, University Regional Hospital Center of Nancy, Nancy F-54000, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Louis","family":"Gu\u00e9ant","sequence":"additional","affiliation":[{"name":"Inserm 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