Hypomorphic GINS3 variants alter DNA replication and cause Meier-Gorlin syndrome.

Autor: McQuaid ME; Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada., Ahmed K; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada., Tran S; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada., Rousseau J; CHU Sainte-Justine, Montreal, Quebec, Canada., Shaheen R; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Kernohan KD; CHEO Research Institute, Ottawa, Ontario, Canada.; Newborn Screening Ontario, CHEO, Ottawa, Ontario, Canada., Yuki KE; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada., Grover P; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada., Dreseris ES; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada., Ahmed S; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada., Dupuis L; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada., Stimec J; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada., Shago M; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada., Al-Hassnan ZN; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Tremblay R; Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada., Maass PG; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada., Wilson MD; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada., Grunebaum E; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada., Boycott KM; CHEO Research Institute, Ottawa, Ontario, Canada., Boisvert FM; University of Sherbrooke, Sherbrooke, Quebec, Canada., Maddirevula S; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Faqeih EA; Section of Medical Genetics, Children's Specialist Hospital, and., Almanjomi F; Department of Pediatric Hematology and Oncology, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia., Khan ZU; Department of Pediatric Hematology and Oncology, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia., Alkuraya FS; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia., Campeau PM; CHU Sainte-Justine, Montreal, Quebec, Canada., Kannu P; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.; Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada., Campos EI; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada., Wurtele H; Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada.; Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2022 May 23; Vol. 7 (10). Date of Electronic Publication: 2022 May 23.
DOI: 10.1172/jci.insight.155648
Abstrakt: The eukaryotic CDC45/MCM2-7/GINS (CMG) helicase unwinds the DNA double helix during DNA replication. The GINS subcomplex is required for helicase activity and is, therefore, essential for DNA replication and cell viability. Here, we report the identification of 7 individuals from 5 unrelated families presenting with a Meier-Gorlin syndrome-like (MGS-like) phenotype associated with hypomorphic variants of GINS3, a gene not previously associated with this syndrome. We found that MGS-associated GINS3 variants affecting aspartic acid 24 (D24) compromised cell proliferation and caused accumulation of cells in S phase. These variants shortened the protein half-life, altered key protein interactions at the replisome, and negatively influenced DNA replication fork progression. Yeast expressing MGS-associated variants of PSF3 (the yeast GINS3 ortholog) also displayed impaired growth, S phase progression defects, and decreased Psf3 protein stability. We further showed that mouse embryos homozygous for a D24 variant presented intrauterine growth retardation and did not survive to birth, and that fibroblasts derived from these embryos displayed accelerated cellular senescence. Taken together, our findings implicate GINS3 in the pathogenesis of MGS and support the notion that hypomorphic variants identified in this gene impaired cell and organismal growth by compromising DNA replication.
Databáze: MEDLINE