Damaging de novo missense variants in EEF1A2lead to a developmental and degenerative epileptic-dyskinetic encephalopathy
| Autor: | Laurine Perrin, Sha Tang, Brandon S. Guida, Tjitske Kleefstra, Marjolein H. Willemsen, Heather Stickney, Michael C. Kruer, Keri Ramsey, Heather C Mefford, Lynette G. Sadleir, Bobby P. C. Koeleman, Evelyn Sattlegger, Angela E. Lin, Sara A. Lewis, Marcello Scala, Sergio Padilla-Lopez, Luis O. Rohena, Joaquim Sa, Marie Laure Mathieu, Floor E. Jansen, Joy Y. Sebe, David W. Raible, Giorgio Casari, Gemma L. Carvill, Ingrid E. Scheffer, Paul A. Caruso, Robert Huether, Mariasavina Severino, Candace T. Myers, Eva H. Brilstra, Ashwin A. Bhandiwad, Katherine L. Helbig, Somayeh Bakhtiari, Sehribani Ulusoy Oktay, Gaetan Lesca, Vinodh Narayanan, Georgina Hollingsworth, Tyler N. Kruer, Christel Depienne, Valeria Capra, Pasquale Striano, Timothy Feyma, Deepak Gill, Andrea Accogli, Caroline Nava |
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| Přispěvatelé: | Carvill, G. L., Helbig, K. L., Myers, C. T., Scala, M., Huether, R., Lewis, S., Kruer, T. N., Guida, B. S., Bakhtiari, S., Sebe, J., Tang, S., Stickney, H., Oktay, S. U., Bhandiwad, A. A., Ramsey, K., Narayanan, V., Feyma, T., Rohena, L. O., Accogli, A., Severino, M., Hollingsworth, G., Gill, D., Depienne, C., Nava, C., Sadleir, L. G., Caruso, P. A., Lin, A. E., Jansen, F. E., Koeleman, B., Brilstra, E., Willemsen, M. H., Kleefstra, T., Sa, J., Mathieu, M. -L., Perrin, L., Lesca, G., Striano, P., Casari, G., Scheffer, I. E., Raible, D., Sattlegger, E., Capra, V., Padilla-Lopez, S., Mefford, H. C., Kruer, M. C. |
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male de novo Heterozygote Adolescent Encephalopathy Choreoathetosis Mutation Missense EEF1A2 Haploinsufficiency Biology Article 03 medical and health sciences Epilepsy All institutes and research themes of the Radboud University Medical Center Peptide Elongation Factor 1 Genetics medicine Missense mutation Humans Child Genetics (clinical) 030304 developmental biology Dystonia 0303 health sciences Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] 030305 genetics & heredity Genetic Complementation Test medicine.disease yeast complementation assay Protein Structure Tertiary dyskinesia Child Preschool epilepsy Cerebellar atrophy Epilepsy Generalized Female medicine.symptom Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] |
| Zdroj: | Human Mutation, 41, 1263-1279 Hum Mutat Human Mutation, 41, 7, pp. 1263-1279 |
| ISSN: | 1059-7794 |
| Popis: | Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein-damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic-dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors. |
| Databáze: | OpenAIRE |
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