ملخص
Purpose: Developmentally regulated Guanosine-5'-triphosphate-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 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 4 individuals with germline DRG1 variants and use in silico, in vitro, and cell-based studies to study the pathogenicity of these alleles. Results: We identified private germline DRG1 variants, including 3 stop-gained p.Gly54∗, p.Arg140∗, p.Lys263∗, and a p.Asn248Phe missense variant. These alleles are recessively inherited in 4 affected individuals from 3 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 messenger RNA/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 preweaning 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.
اللغة الأصلية | English |
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رقم المقال | 100893 |
دورية | Genetics in Medicine |
مستوى الصوت | 25 |
رقم الإصدار | 9 |
المعرِّفات الرقمية للأشياء | |
حالة النشر | Published - سبتمبر 1 2023 |
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في: Genetics in Medicine, المجلد 25, رقم 9, 100893, ٠١.٠٩.٢٠٢٣.
نتاج البحث: المساهمة في مجلة › Article › مراجعة النظراء
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TY - JOUR
T1 - Inactivation of DRG1, encoding a translation factor GTPase, causes a recessive neurodevelopmental disorder
AU - Westrip, Christian A.E.
AU - Paul, Franziska
AU - Al-Murshedi, Fathiya
AU - Qaitoon, Hashim
AU - Cham, Breana
AU - Fletcher, Sally C.
AU - Hendrix, Eline
AU - Boora, Uncaar
AU - Ng, Alvin Yu Jin
AU - Bonnard, Carine
AU - Najafi, Maryam
AU - Alawbathani, Salem
AU - Lambert, Imelda
AU - Fox, Gabriel
AU - Venkatesh, Byrappa
AU - Bertoli-Avella, Aida
AU - Tan, Ee Shien
AU - Al-Maawali, Almundher
AU - Reversade, Bruno
AU - Coleman, Mathew L.
N1 - Funding Information: 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). Conceptualization, Methodology and Supervision: A.A.-M. B.R. F.P. C.A.E.W. M.L.C.; Recruitment, Clinical, and Diagnostic Evaluations: F.A.-M. H.Q. B.C. E.S.T. M.N. S.A. I.L. G.F. A.A.-M. A.B.-A.; Data Curation: C.A.E.W. F.P. A.Y.J.N. C.B. B.V. B.R. A.B.-A. A.A.-M. S.C.F. E.H. U.B.; Funding Acquisition: A.A.-M. B.R. F.P. M.L.C.; Writing-original draft: A.A.-M. B.R. F.P. C.A.E.W. M.L.C.; Writing-review and editing: C.A.E.W. F.P. F.A.-M. H.Q. B.C. S.C.F. E.H. U.B. A.Y.J.N. C.B. M.N. S.A. I.L. G.F. B.V. A.B.-A. E.S.T. A.A.-M. B.R. M.L.C. This study was approved by the Medical Research Ethical Committee of Sultan Qaboos University (family 1), KK Women's and Children's Hospital (family 2), and Centogene (Germany) (family 3). Parents provided written informed consent to participate and to publish their family pedigrees and clinical data. A valid Health Insurance Portability and Accountability Act authorization for participation/publication from every individual whose protected health information and photograph is included has been received and archived. 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). Genetic analyses were performed in accordance with bioethics rules of national laws. Further approvals were obtained from the West Midlands, Coventry, and Warwickshire Research Ethics Committee (REC: Stewart/20/WM/0098), Maryam Najafi and Salem Alawbathani are employees of Centogene. All other authors declare no conflicts of interest. 1000 Genomes Project Database, http://browser.1000genomes.org/index.html, CRISPRScan, https://www.crisprscan.org, Exome Aggregation Consortium (ExAC), http://exac.broadinstitute.org, Exome Variant Server from NHLBI Exome Sequencing Project (ESP), https://evs.gs.washington.edu/EVS/, https://cadd.gs.washington.edu/score, Genome Aggregation Database (GnomAD), http://gnomad.broadinstitute.org/, Greater Middle East (GME) Variome web, http://igm.ucsd.edu/gme/index.php, NCBI dbSNP, https://www.ncbi.nlm.nih.gov/SNP/, Online Mendelian Inheritance in Man (OMIM), https://www.omim.org, The online version of this article (https://doi.org/10.1016/j.gim.2023.100893) contains supplemental material, which is available to authorized users. Funding Information: 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). Publisher Copyright: © 2023 The Authors
PY - 2023/9/1
Y1 - 2023/9/1
N2 - Purpose: Developmentally regulated Guanosine-5'-triphosphate-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 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 4 individuals with germline DRG1 variants and use in silico, in vitro, and cell-based studies to study the pathogenicity of these alleles. Results: We identified private germline DRG1 variants, including 3 stop-gained p.Gly54∗, p.Arg140∗, p.Lys263∗, and a p.Asn248Phe missense variant. These alleles are recessively inherited in 4 affected individuals from 3 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 messenger RNA/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 preweaning 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.
AB - Purpose: Developmentally regulated Guanosine-5'-triphosphate-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 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 4 individuals with germline DRG1 variants and use in silico, in vitro, and cell-based studies to study the pathogenicity of these alleles. Results: We identified private germline DRG1 variants, including 3 stop-gained p.Gly54∗, p.Arg140∗, p.Lys263∗, and a p.Asn248Phe missense variant. These alleles are recessively inherited in 4 affected individuals from 3 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 messenger RNA/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 preweaning 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.
KW - DRG1
KW - GTPase
KW - Mendelian genetics
KW - Mouse modeling
KW - Neurodevelopment disorder
KW - Humans
KW - Animals
KW - Mammals/metabolism
KW - Mice
KW - GTP-Binding Proteins
KW - GTP Phosphohydrolases/genetics
KW - RNA, Messenger
KW - Carrier Proteins
KW - Neurodevelopmental Disorders/genetics
UR - http://www.scopus.com/inward/record.url?scp=85164426882&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85164426882&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/952ae741-db7b-3c94-99f8-cab957d913f2/
U2 - 10.1016/j.gim.2023.100893
DO - 10.1016/j.gim.2023.100893
M3 - Article
C2 - 37179472
AN - SCOPUS:85164426882
SN - 1098-3600
VL - 25
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 9
M1 - 100893
ER -