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Biallelic NUDT2 variants defective in mRNA decapping cause a neurodevelopmental disease

Lookup NU author(s): Professor Robert Taylor

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Abstract

© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.Dysfunctional RNA processing caused by genetic defects in RNA processing enzymes has a profound impact on the nervous system, resulting in neurodevelopmental conditions. We characterized a recessive neurological disorder in 18 children and young adults from 10 independent families typified by intellectual disability, motor developmental delay and gait disturbance. In some patients peripheral neuropathy, corpus callosum abnormalities and progressive basal ganglia deposits were present. The disorder is associated with rare variants in NUDT2, a mRNA decapping and Ap4A hydrolysing enzyme, including novel missense and in-frame deletion variants. We show that these NUDT2 variants lead to a marked loss of enzymatic activity, strongly implicating loss of NUDT2 function as the cause of the disorder. NUDT2-deficient patient fibroblasts exhibit a markedly altered transcriptome, accompanied by changes in mRNA half-life and stability. Amongst the most up-regulated mRNAs in NUDT2-deficient cells, we identified host response and interferon-responsive genes. Importantly, add-back experiments using an Ap4A hydrolase defective in mRNA decapping highlighted loss of NUDT2 decapping as the activity implicated in altered mRNA homeostasis. Our results confirm that reduction or loss of NUDT2 hydrolase activity is associated with a neurological disease, highlighting the importance of a physiologically balanced mRNA processing machinery for neuronal development and homeostasis.

Publication metadata

Author(s): Husain RA, Jiao X, Hennings JC, Giesecke J, Palsule G, Beck-Wodl S, Osmanovic D, Bjorgo K, Mir A, Ilyas M, Abbasi SM, Efthymiou S, Dominik N, Maroofian R, Houlden H, Rankin J, Pagnamenta AT, Nashabat M, Altwaijri W, Alfadhel M, Umair M, Khouj E, Reardon W, El-Hattab AW, Mekki M, Houge G, Beetz C, Bauer P, Putoux A, Lesca G, Sanlaville D, Alkuraya FS, Taylor RW, Mentzel H-J, Hubner CA, Huppke P, Hart RP, Haack TB, Kiledjian M, Rubio I

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2024

Volume: 147

Issue: 4

Pages: 1197-1205

Print publication date: 01/04/2024

Online publication date: 23/12/2023

Acceptance date: 05/12/2023

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press

URL: https://doi.org/10.1093/brain/awad434

DOI: 10.1093/brain/awad434

PubMed id: 38141063

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