Inactivation of DRG1, encoding a translation factor GTPase, causes a Recessive Neurodevelopmental Disorder

Abstract

DRG1 is a highly conserved member of a class of GTPases implicated in ribosome biogenesis and translation. The expression of mammalian DRG1 is elevated in the central nervous system during development, and its function has been implicated in fundamental cellular processes including protein synthesis and cellular proliferation. Using exome sequencing, we identified rare and likely pathogenic germline DRG1 variants including three stop-gained p.Gly54*, p.Arg140*, p.Lys263* and a p.Asn248Phe missense variant. These alleles segregate recessively in four affected individuals from three unrelated families and cause a neurodevelopmental disorder with global developmental delay, microcephaly, short stature and craniofacial anomalies. Using functional assays, we show that these loss-of-function variants: 1) severely disrupt DRG1 mRNA/protein stability in patient-derived fibroblasts, 2) impair its GTPase activity in vitro and 3) compromise its binding to partner protein ZC3H15. Consistent with the importance of DRG1 in humans, targeted inactivation of Drg1 in mice resulted in pre-weaning lethality. Our work highlights the importance of DRG1 GTPase activity for normal development and underscores the significance of translation factor GTPases in human physiology and homeostasis.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

M.L.C is a Cancer Research UK Fellow. B.R. is an investigator of the National Research Foundation (NRF, Singapore) and Branco Weiss Foundation (Switzerland) and an EMBO Young Investigator. We thank the SRIS Asian Skin Biobank (ASB), especially Alicia YAP Mei Yi, Joycelyn LEE Xiang Yi, and Siti Nur Aishah Binte ALIMAT, for isolating and expanding the primary fibroblasts. The ASB work was funded by the A*STAR IAF-PP Project (H1701a0004). This work was funded by a CRUK Programme Foundation Award to M.L.C. (C33483/A25674), a Strategic Positioning Fund for Genetic Orphan Diseases and an inaugural A*STAR Investigatorship from the Agency for Science, Technology and Research in Singapore to B.R. and the 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 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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This study was approved in Oman by the ethics committees of the Medical Research Ethical Committee of the Sultan Qaboos University for Family 1, of KK Women's and Children's Hospital for Family 2, and Centogene (Germany) for Family 3. The parents of each family provided written informed consent to participate in this study and to publish their family pedigrees and clinical data. All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki. The study protocol was approved by A*STAR institutional review board (IRB 2019-087) and genetic analyses were performed in accordance with bioethics rules of national laws.

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Data Availability

The data that support the findings of this study are available from the corresponding authors upon request.

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