Purpose: Developmentally-regulated GTP-binding protein 1 (DRG1) is a highly conserved member of a class of GTPases implicated in translation. Although the expression of mammalian DRG1 is elevated in the central nervous system (CNS) during development, and its function has been implicated in fundamental cellular processes, no pathogenic germline variants have yet been identified. Here, we characterize the clinical and biochemical consequences of DRG1 variants. Methods: We collate clinical information of four individuals with germline DRG1 variants and employ in silico, in vitro, and cell-based studies to study the pathogenicity of these alleles. Results: We identified private germline DRG1 variants including three stop-gained p.Gly54*, p.Arg140*, p.Lys263* and a p.Asn248Phe missense variant. These alleles are recessively inherited in four affected individuals from three distinct families and cause a neurodevelopmental disorder with global developmental delay, primary microcephaly, short stature and craniofacial anomalies. We show that these loss-of-function variants: 1) severely disrupt DRG1 mRNA/protein stability in patient-derived fibroblasts, 2) impair its GTPase activity and 3) compromise its binding to partner protein ZC3H15. Consistent with the importance of DRG1 in humans, targeted inactivation of mouse Drg1 resulted in pre-weaning lethality. Conclusion: Our work defines a new Mendelian disorder of DRG1 deficiency. This study highlights DRG1’s importance for normal mammalian development and underscores the significance of translation factor GTPases in human physiology and homeostasis.
|Original language||English (US)|
|Journal||Genetics in medicine : official journal of the American College of Medical Genetics|
|State||Published - May 11 2023|
Bibliographical noteKAUST Repository Item: Exported on 2023-05-18
Acknowledgements: B.R. is an investigator of the National Research Foundation (NRF, Singapore) and Branco Weiss Foundation (Switzerland) and an EMBO Young Investigator. The ASB work was funded by the A*STAR IAF-PP Project (H1701a0004). M.L.C. is funded by a CRUK Programme Foundation Award (C33483/A2567). This work was funded by a Singhealth Duke-NUS Genomic Medicine Centre Fund (SDDC/FY2021/EX/93-A147).
F. P. is a recipient of a long-term European Molecular Biology Organization (EMBO) postdoc fellowship and a short-term EMBO travel fellowship. Her research is supported by the Singapore Ministry of Health’s National Medical Research Council under its Young Individual Research Grant scheme (Project ID MOH-000549-01) and A*STAR under its Career Development Award (Project number C210112002). A.A.M is a recipient of Sultan Qaboos University Strategic research funding (project code SR/MED/GENT/16/01).
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