Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.

Autor:	Muffels IJJ; Department of Metabolic Diseases, Division Pediatrics, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, the Netherlands; Center for Translational Immunology (CTI), Division Pediatrics, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Schene IF; Department of Metabolic Diseases, Division Pediatrics, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, the Netherlands., Rehmann H; Department of Energy and Biotechnology, Flensburg University of Applied Sciences, Flensburg, Germany., Massink MPG; Department of Genetics, Division Pediatrics, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., van der Wal MM; Center for Translational Immunology (CTI), Division Pediatrics, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Bauder C; Department of Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, Munich, Germany., Labeur M; Department of Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany., Armando NG; Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina., Lequin MH; Division Imaging and Oncology University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Houben ML; Department of General Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Giltay JC; Department of Genetics, Division Pediatrics, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Haitjema S; Central Diagnostics Laboratory, University Medical Center Utrecht, Utrecht, the Netherlands., Huisman A; Central Diagnostics Laboratory, University Medical Center Utrecht, Utrecht, the Netherlands., Vansenne F; Department of Medical Genetics, University Medical Center Groningen, Groningen, the Netherlands., Bluvstein J; Dravet Center and Comprehensive Epilepsy Center, NYU School of Medicine, New York, NY, USA., Pappas J; NYU Clinical Genetic Services, NYU Grossman School of Medicine, New York, NY, USA., Shailee LV; Department of Radiology, NYU Grossman School of Medicine, New York, NY, USA., Zarate YA; Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA., Mokry M; Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands., van Haaften GW; Department of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., Nieuwenhuis EES; Department of Biomedical and Life Sciences, University College Roosevelt, Middelburg, the Netherlands., Refojo D; Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina; Molecular Neurobiology, Max Planck Institute of Psychiatry, Munich, Germany., van Wijk F; Department of Genetics, Division Pediatrics, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Fuchs SA; Department of Metabolic Diseases, Division Pediatrics, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, the Netherlands., van Hasselt PM; Department of Metabolic Diseases, Division Pediatrics, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, the Netherlands. Electronic address: p.vanhasselt@umcutrecht.nl.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2023 Jan 05; Vol. 110 (1), pp. 146-160.
DOI:	10.1016/j.ajhg.2022.12.003
Abstrakt:	Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes. To delineate how cellular consequences of NAE1 deficiency would lead to the clinical phenotype, we focused primarily on the rarest phenotypic features, based on the assumption that these would best reflect the pathophysiology at stake. Two of the rarest features, neuronal loss and lymphopenia worsening during infections, suggest that NAE1 is required during cellular stress caused by infections to protect against cell death. In support, we found that stressing the proteasome system with MG132-requiring upregulation of neddylation to restore proteasomal function and proteasomal stress-led to increased cell death in fibroblasts of individuals with NAE1 genetic variants. Additionally, we found decreased lymphocyte counts after CD3/CD28 stimulation and decreased NF-κB translocation in individuals with NAE1 variants. The rarest phenotypic feature-delayed closure of the ischiopubic rami-correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data of fibroblasts. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show that NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests that a focus on rare phenotypic features is able to provide significant pathophysiological insights in diseases caused by mutations in genes with pleiotropic effects. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 American Society of Human Genetics. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu