Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 146-160 |
| Number of pages | 15 |
| Journal | American Journal of Human Genetics |
| Volume | 110 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 5 2023 |
Bibliographical note
Publisher Copyright:© 2022 American Society of Human Genetics
Funding
This work was supported by the Max Planck Society (D.R.), the VolkswagenStiftung (D.R.), the Agencia Nacional de Promoción Científica y Tecnológica , Argentina (D.R.) and the Fondo para la convergencia estructural del mercosur -FOCEM ( COF 03/11 ) (D.R.). We would like to thank the parents of individual 1 for drafting Figure 6A. This work was supported by the Max Planck Society (D.R.), the VolkswagenStiftung (D.R.), the Agencia Nacional de Promoción Científica y Tecnológica, Argentina (D.R.) and the Fondo para la convergencia estructural del mercosur-FOCEM (COF 03/11) (D.R.). We would like to thank the parents of individual 1 for drafting Figure 6A. Concept: P.M.v.H. and I.J.J.M. Designing experiments: I.J.J.M. I.F.S. M.M.v.d.W. C.B. M.L. D.R. F.v.W. S.A.F. E.E.S.N. and P.M.v.H. Conducting experiments: I.J.J.M. I.F.S. M.M.v.d.W. C.B. M.L. N.G.A. Acquiring (medical) data of study participants and cells: I.J.J.M. Y.A.Z. L.V.S. J.B. J.P. M.L.H. J.C.G. S.H. A.H. F.V. M.P.G.M. M.L. P.M.v.H. Analyzing data: I.J.J.M. I.F.S. M.P.G.M. M.M.v.d.W. Genetic testing and interpretation of variants: M.P.G.M. G.v.H. Molecular predictions: M.P.G.M. H.R. Writing the manuscript: I.J.J.M. and P.M.v.H. Supervision of experiments and writing process: P.M.v.H. S.A.F. F.v.W. E.E.S.N. D.R. S.A.F. D.R. and F.v.W. spent equal time and effort on supervision of the manuscript. The authors declare no competing interests.
| Funders |
|---|
| FOCEM |
| Fritz-Haber-Institut der Max-Planck-Gesellschaft |
| Volkswagen Foundation |
| Agencia Nacional de Promoción Científica y Tecnológica |
Keywords
- NAE1
- lymphopenia
- neddylation
- neurodegeneration
- ocurrence ratio
- phenotypic specificity
- post-translational protein modification
- proteasome
- ubiquitination
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)