De Novo variants in EEF2 cause a neurodevelopmental disorder with benign external hydrocephalus
| Autor: | Rolph Pfundt, Jonathan D. Dinman, Arjan P.M. de Brouwer, Grace Yoon, Maria J. Nabais Sá, Alexandra Schneider, Michèl A.A.P. Willemsen, Graeme A.M. Nimmo, Alexandra N. Olson, Christopher M. Gomez, Bert B.A. de Vries, Francisca Millan |
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| Rok vydání: | 2021 |
| Předmět: |
Elongation Factor 2 Kinase
Male Heterozygote Biology EEF2 03 medical and health sciences Neurodevelopmental disorder Exome Sequencing Genetics medicine Humans Missense mutation Exome Child Molecular Biology Gene Genetics (clinical) Exome sequencing 030304 developmental biology 0303 health sciences Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] Cerebellar ataxia 030305 genetics & heredity Translation (biology) General Medicine medicine.disease Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] Phenotype Neurodevelopmental Disorders Child Preschool Mutation General Article medicine.symptom Hydrocephalus Ventriculomegaly |
| Zdroj: | Human Molecular Genetics, 29, 24, pp. 3892-3899 Human Molecular Genetics, 29, 3892-3899 Hum Mol Genet |
| ISSN: | 0964-6906 |
| Popis: | Contains fulltext : 231523.pdf (Publisher’s version ) (Closed access) Eukaryotic translation elongation factor 2 (eEF2) is a key regulatory factor in gene expression that catalyzes the elongation stage of translation. A functionally impaired eEF2, due to a heterozygous missense variant in the EEF2 gene, was previously reported in one family with spinocerebellar ataxia-26 (SCA26), an autosomal dominant adult-onset pure cerebellar ataxia. Clinical exome sequencing identified de novo EEF2 variants in three unrelated children presenting with a neurodevelopmental disorder (NDD). Individuals shared a mild phenotype comprising motor delay and relative macrocephaly associated with ventriculomegaly. Populational data and bioinformatic analysis underscored the pathogenicity of all de novo missense variants. The eEF2 yeast model strains demonstrated that patient-derived variants affect cellular growth, sensitivity to translation inhibitors and translational fidelity. Consequently, we propose that pathogenic variants in the EEF2 gene, so far exclusively associated with late-onset SCA26, can cause a broader spectrum of neurologic disorders, including childhood-onset NDDs and benign external hydrocephalus. |
| Databáze: | OpenAIRE |
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