Please use this identifier to cite or link to this item:
Title: Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy.
Austin Authors: Carvill, Gemma L;Helbig, Katherine L;Myers, Candace T;Scala, Marcello;Huether, Robert;Lewis, Sara;Kruer, Tyler N;Guida, Brandon S;Bakhtiari, Somayeh;Sebe, Joy;Tang, Sha;Stickney, Heather;Oktay, Sehribani Ulusoy;Bhandiwad, Ashwin A;Ramsey, Keri;Narayanan, Vinodh;Feyma, Timothy;Rohena, Luis O;Accogli, Andrea;Severino, Mariasavina;Hollingsworth, Georgina;Gill, Deepak;Depienne, Christel;Nava, Caroline;Sadleir, Lynette G;Caruso, Paul A;Lin, Angela E;Jansen, Floor E;Koeleman, Bobby;Brilstra, Eva;Willemsen, Marjolein H;Kleefstra, Tjitske;Sa, Joaquim;Mathieu, Marie-Laure;Perrin, Laurine;Lesca, Gaetan;Striano, Pasquale;Casari, Giorgio;Scheffer, Ingrid E ;Raible, David;Sattlegger, Evelyn;Capra, Valeria;Padilla-Lopez, Sergio;Mefford, Heather C;Kruer, Michael C
Affiliation: IRCCS Ospedale Policlinico San Martino, Genoa, Italy
Department of Pediatrics, Division of Genetics, San Antonio Military Medical Center, San Antonio, TX, USA
Departments of Medicine and Paediatrics, University of Melbourne and Royal Children's Hospital, Melbourne, Australia
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Pediatrics, Long School of Medicine, University of Texas, San Antonio, TX, USA
Medical Genetics, Department of Pediatrics, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA
Ken and Ruth Davee Department of Neurology, Northwestern University, Chicago, IL, USA
Ty Nelson Department of Neurology, The Children's Hospital at Westmead, Sydney, NSW, Australia
School of Natural & Computational Sciences, Massey University, Auckland, New Zealand
Department of Paediatrics and Child Health, University of Otago Wellington, Wellington South, New Zealand
INSERM UMR 975, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France
Department of Paediatric Physical Medicine and Rehabilitation, CHU Saint-Etienne, Hôpital Bellevue, France
CRNL Inserm U1028 - CNRS UMR5292 - Claude Bernard University Lyon 1, Lyon, France and Department of Medical Genetics, Lyon University Hospital, Lyon, France
Claude Bernard Lyon 1 University, Lyon, France
Division of Genetic Medicine, University of Washington, Seattle, WA, USA
Ambry Genetics, Aliso Viejo, CA, USA
Department of Biology, University of Washington, Seattle, WA, USA
Department of Biological Structure, University of Washington, Seattle, WA, USA
Gillette Children's Specialty Healthcare, St. Paul, MN, USA
Translational Genomics Research Institute, Phoenix, AZ, USA
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini, Genoa, Italy
Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA
Departments of Child Health, Cellular & Molecular Medicine, and Neurology and Program in Genetics, University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA
Neuropaediatrics Department, Femme Mère Enfant Hospital, Lyon, France
DINOGMI Università degli Studi di Genova, Genoa, Italy
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
The Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Department of Pediatric Neurology, University Medical Center, Utrecht, the Netherlands
Department of Genetics, Utrecht University, The Netherlands
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Serviço de Genética Médica, Centro Hospitalar e Universitário de Coimbra, Portugal
Issue Date: Jul-2020 2020-03-20
Publication information: Human mutation 2020; 41(7): 1263-1279
Abstract: 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. This article is protected by copyright. All rights reserved.
DOI: 10.1002/humu.24015
ORCID: 0000-0003-4945-3628
Journal: Human mutation
PubMed URL: 32196822
Type: Journal Article
Subjects: EEF1A2
de novo
yeast complementation assay
Appears in Collections:Journal articles

Show full item record

Page view(s)

checked on Jan 29, 2023

Google ScholarTM


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.