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

MUFFELS I; SCHENE IF; REHMANN H; MASSINK MPG; VAN DER WAL MM; BAUDER C; LABEUR M,; ARMANDO N; LEQUIN MH; HOUBEN ML; HAITJEMA S; HUISMAN A; VANSENNE F; BLUVSTEIN J; PAPPAS J; SHAILEE LB; ZARATE YI; MOKRY M; VAN HAAFTEN G; NIEUWENHUIS EES; REFOJO D,; V. WIJK F; FUCHS SA; VAN HASSELT P

AMERICAN JOURNAL OF HUMAN GENETICS

CELL PRESS

Lugar: United States; Año: 2023

0002-9297

Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four patients with bi-allelic variants in the NAE1 gene, encoding neddylation’s E1 enzyme. Patients showed decreased NAE1 expression, a changed ratio of unneddylated to neddylated cullins and proteasome dysfunction. Next, we aimed to delinate the cellular consequences of faulty neddylation and how these would lead to the clinical phenotype. We chose to focus primarily on the most rare phenotypic features, that would best reflect the pathophysiology at stake. Rare features included neuronal loss and lymphopenia during infections, indicating that NAE1 protects against stress-mediated cellular apoptosis. In support, NAE1 deficient cells showed decreased viability during various stress-inducing events, such as CD3/CD28 stimulation. The rarest phenotypic feature - delayed closure of the ischiopubic rami – correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests a focus on rare phenotypic features is able to capture the biological essence in diseases caused by mutations in pleiotropic genes.