This paper is only available as a PDF. To read, Please Download here.
Abstract
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.
Keywords
Article info
Publication history
Accepted:
May 7,
2023
Received in revised form:
May 5,
2023
Received:
October 11,
2022
Publication stage
In Press Accepted ManuscriptIdentification
Copyright
© 2023 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.
User license
Creative Commons Attribution (CC BY 4.0) | How you can reuse 
Elsevier's open access license policy
Creative Commons Attribution (CC BY 4.0)
Permitted
- Read, print & download
- Redistribute or republish the final article
- Text & data mine
- Translate the article
- Reuse portions or extracts from the article in other works
- Sell or re-use for commercial purposes
Elsevier's open access license policy
