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Muffels, I.J.J.* ; Schene, I.F.* ; Rehmann, H.* ; Massink, M.P.G.* ; van der Wal, M.M.* ; Bauder, C. ; Labeur, M.* ; Armando, N.G.* ; Lequin, M.H.* ; Houben, M.L.* ; Giltay, J.C.* ; Haitjema, S.* ; Huisman, A.* ; Vansenne, F.* ; Bluvstein, J.* ; Pappas, J.* ; Shailee, L.V.* ; Zarate, Y.A.* ; Mokry, M.* ; van Haaften, G.W.* ; Nieuwenhuis, E.E.S.* ; Refojo, D.* ; van Wijk, F.* ; Fuchs, S.A.* ; van Hasselt, P.M.*

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

Am. J. Hum. Genet. 110, 146-160 (2023)
Postprint Research data DOI PMC
Open Access Green
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Lymphopenia ; Nae1 ; Neddylation ; Neurodegeneration ; Ocurrence Ratio ; Phenotypic Specificity ; Post-translational Protein Modification ; Proteasome ; Ubiquitination; Campomelic Dysplasia; Protein-activation; Ubiquitin; Neddylation; Nedd8; Apoptosis; Program; Pathway; Parkin; Pink1
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 110, Issue: 1, Pages: 146-160 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
POF-Topic(s) 30204 - Cell Programming and Repair
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500500-001
Grants Max-Planck-Gesellschaft
Agencia Nacional de Promoción Científica y Tecnológica
Volkswagen Foundation
FOCEM
DOI 10.1016/j.ajhg.2022.12.003
WOS ID 000940317000001
Scopus ID 85145272959
PubMed ID 36608681
Erfassungsdatum 2023-01-08
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