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2 results on '"Pichard S"'

1. Transition in health care from childhood to adulthood (TCA) for lysosomal diseases patients in France. Current state and priorities : The TENALYS study

Author

Belmatoug, N., Marcel, C., Arnoux, A., Brassier, A., Pichard, S., Feillet, F., Labarthe, F., Chabrol, B., Berger, M., Héron, B., Genevaz, D., CHADEYRON, DOMINIQUE, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), and Université Clermont Auvergne [2017-2020] (UCA [2017-2020])

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2020

2. Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency

Author

Olsen, R. K., Konarikova, E., Giancaspero, T. A., Mosegaard, S., Boczonadi, V., Matakovic, L., Veauville-Merllie, A., Terrile, C., Schwarzmayr, T., Haack, T. B., Auranen, M., Leone, P., Galluccio, M., Imbard, A., Gutierrez-Rios, P., Palmfeldt, J., Graf, E., Vianey-Saban, Christine, Oppenheim, M., Schiff, M., Pichard, S., Rigal, O., Pyle, A., Chinnery, P. F., Konstantopoulou, V., Moslinger, D., Feichtinger, R. G., Talim, B., Topaloglu, H., Coskun, T., Gucer, S., Botta, A., Pegoraro, E., Malena, A., Vergani, L., Mazza, D., Zollino, M., Ghezzi, D., Acquaviva, C., Tyni, T., Boneh, A., Meitinger, T., Strom, T. M., Gregersen, N., Mayr, J. A., Horvath, R., Barile, M., Prokisch, H., Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Clinicum, Neurologian yksikkö, Children's Hospital, Lastenneurologian yksikkö, HUS Children and Adolescents, and Pillet, Lauriane

Subjects
Male, Mitochondrial Diseases, Genetics, Genetics (clinical), Riboflavin, [SDV]Life Sciences [q-bio], Messenger, Settore MED/03 - GENETICA MEDICA, DISEASE, FUNCTIONAL-CHARACTERIZATION, MITOCHONDRIA, Site-Directed, Genetics(clinical), heterocyclic compounds, Frameshift Mutation, Multiple Acyl Coenzyme A Dehydrogenase Deficiency, Cells, Cultured, Skin, Cultured, Blotting, Reverse Transcriptase Polymerase Chain Reaction, Skeletal, Nucleotidyltransferases, [SDV] Life Sciences [q-bio], Liver, ESCHERICHIA-COLI, Adult, Blotting, Western, Case-Control Studies, Electron Transport, Female, Fibroblasts, Flavin-Adenine Dinucleotide, Gene Expression Profiling, Humans, Infant, Infant, Newborn, Muscle, Skeletal, Mutagenesis, Site-Directed, Protein Binding, RNA, Messenger, Real-Time Polymerase Chain Reaction, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Vitamin B Complex, Young Adult, Muscle, Western, Cells, Article, VIALETTO-VAN LAERE, Matrix-Assisted Laser Desorption-Ionization, COFACTORS, Spectrometry, ISOFORM 2, Mass, Newborn, ELECTRON-TRANSFER FLAVOPROTEIN, OVER-EXPRESSION, enzymes and coenzymes (carbohydrates), Mutagenesis, RNA, bacteria, 3111 Biomedicine, SYNTHETASE
Abstract

International audience; Multiple acyl-CoA dehydrogenase deficiencies (MADDs) are a heterogeneous group of metabolic disorders with combined respiratory-chain deficiency and a neuromuscular phenotype. Despite recent advances in understanding the genetic basis of MADD, a number of cases remain unexplained. Here, we report clinically relevant variants in FLAD1, which encodes FAD synthase (FADS), as the cause of MADD and respiratory-chain dysfunction in nine individuals recruited from metabolic centers in six countries. In most individuals, we identified biallelic frameshift variants in the molybdopterin binding (MPTb) domain, located upstream of the FADS domain. Inasmuch as FADS is essential for cellular supply of FAD cofactors, the finding of biallelic frameshift variants was unexpected. Using RNA sequencing analysis combined with protein mass spectrometry, we discovered FLAD1 isoforms, which only encode the FADS domain. The existence of these isoforms might explain why affected individuals with biallelic FLAD1 frameshift variants still harbor substantial FADS activity. Another group of individuals with a milder phenotype responsive to riboflavin were shown to have single amino acid changes in the FADS domain. When produced in E. coli, these mutant FADS proteins resulted in impaired but detectable FADS activity; for one of the variant proteins, the addition of FAD significantly improved protein stability, arguing for a chaperone-like action similar to what has been reported in other riboflavin-responsive inborn errors of metabolism. In conclusion, our studies identify FLAD1 variants as a cause of potentially treatable inborn errors of metabolism manifesting with MADD and shed light on the mechanisms by which FADS ensures cellular FAD homeostasis.

Published
2016

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