An atypical form of 60S ribosomal subunit in Diamond-Blackfan anemia linked to RPL17 variants.

Autor: Fellmann F; The ColLaboratory, University of Lausanne, Lausanne, Switzerland.; Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland., Saunders C; University of Missouri Kansas City, School of Medicine, Kansas City, Missouri, USA.; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, Missouri, USA., O'Donohue MF; MCD, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France., Reid DW; Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, USA.; Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA., McFadden KA; Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA., Montel-Lehry N; MCD, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France., Yu C; BGI-Shenzhen, Shenzhen, China., Fang M; BGI-Shenzhen, Shenzhen, China., Zhang J; BGI-Shenzhen, Shenzhen, China., Royer-Bertrand B; Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland., Farinelli P; Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland., Karboul N; UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France., Willer JR; Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA., Fievet L; Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA., Bhuiyan ZA; Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland., Kleinhenz AL; Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA., Jadeau J; MCD, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France., Fulbright J; Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, Missouri, USA., Rivolta C; Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland., Renella R; Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland., Katsanis N; Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA., Beckmann JS; Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland.; Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.; Clinical Bioinformatics, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland., Nicchitta CV; Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, USA.; Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA., Da Costa L; AP-HP, Service d'Hématologie Biologique, Hôpital Robert Debré, Paris, France.; Université Paris Cité, Paris, France.; Hematim EA4666, CURS, CHU Amiens, Amiens, France.; LABEX GR-EX, Paris, France., Davis EE; Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.; Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.; Departments of Pediatrics and Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Gleizes PE; MCD, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2024 Aug 01; Vol. 9 (17). Date of Electronic Publication: 2024 Aug 01.
DOI: 10.1172/jci.insight.172475
Abstrakt: Diamond-Blackfan anemia syndrome (DBA) is a ribosomopathy associated with loss-of-function variants in more than 20 ribosomal protein (RP) genes. Here, we report the genetic, functional, and biochemical dissection of 2 multigenerational pedigrees with variants in RPL17, a large ribosomal subunit protein-encoding gene. Affected individuals had clinical features and erythroid proliferation defects consistent with DBA. Further, RPL17/uL22 depletion resulted in anemia and micrognathia in zebrafish larvae, and in vivo complementation studies indicated that RPL17 variants were pathogenic. Lymphoblastoid cell lines (LCLs) derived from patients displayed a ribosomal RNA maturation defect reflecting haploinsufficiency of RPL17. The proteins encoded by RPL17 variants were not incorporated into ribosomes, but 10%-20% of 60S ribosomal subunits contained a short form of 5.8S rRNA (5.8SC), a species that is marginal in normal cells. These atypical 60S subunits were actively engaged in translation. Ribosome profiling showed changes of the translational profile, but those are similar to LCLs bearing RPS19 variants. These results link an additional RP gene to DBA. They show that ribosomes can be modified substantially by RPL17 haploinsufficiency but support the paradigm that translation alterations in DBA are primarily related to insufficient ribosome production rather than to changes in ribosome structure or composition.
Databáze: MEDLINE