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

• DOI: 10.1016/j.ajhg.2022.12.003
• Publication Date: 2023-01-05T15:37:22Z
• Authors: Irena J.J. Muffels; Imre F. Schene; Holger Rehmann; Maarten P.G. Massink; Maria M. van der Wal; Corinna Bauder; Martha Labeur; Natalia G. Armando; Maarten H. Lequin; Michiel L. Houben; Jaques C. Giltay; Saskia Haitjema; Albert Huisman; Fleur Vansenne; Judith Bluvstein; John Pappas; Lala V. Shailee; Yuri A. Zarate; Michal Mokry; Gijs W. van Haaften; Edward E.S. Nieuw...; Damian Refojo; Femke van Wijk; Sabine A. Fuchs; Peter M. van Hasselt
• Keywords: 0301 basic medicine; NEDDYLATION; Proteasome Endopeptidase Complex; NEDD8 Protein; POST-TRANSLATIONAL PROTEIN MODIFICATION; UBIQUITINATION; ubiquitination; PHENOTYPIC SPECIFICITY; 03 medical and health sciences; neddylation; OCURRENCE RATIO; post-translational protein modification; https://purl.org/becyt/ford/1.6; Lymphopenia/genetics; Intellectual Disability; Lymphopenia; Genetics; Journal Article; Humans; Genetics(clinical); PROTEASOME; https://purl.org/becyt/ford/1; NEURODEGENERATION; neurodegeneration; NF-kappa B; ocurrence ratio; lymphopenia; phenotypic specificity; Intellectual Disability/genetics; 3. Good health; Proteasome Endopeptidase Complex/metabolism; proteasome; NF-kappa B/metabolism; Signal Transduction/genetics; Lymphopenia ; Nae1 ; Neddylation ; Neurodegeneration ; Ocurrence Ratio ; Phenotypic Specificity ; Post-translational Protein Modification ; Proteasome ; Ubiquitination; NEDD8 Protein/genetics; NAE1; LYMPHOPENIA; Signal Transduction

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.