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Expanding the spectrum of EEF1D neurodevelopmental disorders: biallelic variants in the guanine exchange domain

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Item Type:Article
Title:Expanding the spectrum of EEF1D neurodevelopmental disorders: biallelic variants in the guanine exchange domain
Creators Name:Averdunk, L. and Al-Thihli, K. and Surowy, H. and Lüdecke, H.J. and Drechsler, M. and Yigit, G. and Smorag, L. and Hallak, B.A. and Li, Y. and Altmüller, J. and Guthoff, T. and Wallot, M. and Nürnberg, P. and Wollnik, B. and Abou Jamra, R. and Al-Maawali, A. and Wieczorek, D.
Abstract:Protein translation is an essential cellular process and dysfunctional protein translation causes various neurodevelopmental disorders. The eukaryotic translation elongation factor 1A (eEF1A) delivers aminoacyl-tRNA to the ribosome, while the eEF1B complex acts as a guanine exchange factor (GEF) of GTP for GDP indirectly catalyzing the release of eEF1A from the ribosome. The gene EEF1D encodes the eEF1Bδ subunit of the eEF1B complex. EEF1D is alternatively spliced giving rise to one long and three short isoforms. Two different homozygous, truncating variants in EEF1D had been associated with severe intellectual disability and microcephaly in two families. The published variants only affect the long isoform of EEF1D that acts as a transcription factor of heat shock element proteins. By exome sequencing, we identified two different homozygous variants in EEF1D in two families with severe developmental delay, severe microcephaly, spasticity, and failure to thrive with optic atrophy, poor feeding, and recurrent aspiration pneumonias. The EEF1D variants of this study are localized in the C-terminal GEF domain suggesting that a disturbed protein translation machinery might contribute to the neurodevelopmental phenotype. Pathogenic variants localized in both the alternatively spliced domain or in the GEF domain of EEF1D cause a severe neurodevelopmental disorder with microcephaly and spasticity.
Keywords:Neurodevelopmental Disorders, EEF1D, Cerebral Palsy, Protein Translation, Optic Atrophy, Rare Disease
Source:Clinical Genetics
Page Range:484-491
Date:April 2023
Official Publication:https://doi.org/10.1111/cge.14290
PubMed:View item in PubMed

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