ResearchIn-Press PreviewGeneticsHematology Open Access | 10.1172/jci.insight.172475
1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
Find articles by Reid, D. in: JCI | PubMed | Google Scholar
1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
Find articles by Zhang, J. in: JCI | PubMed | Google Scholar
1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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1The ColLaboratory, University of Lausanne, Lausanne, Switzerland
2School of Medicine, University of Missouri Kansas City, Kansas City, United States of America
3Center for Integrative Biology, University of Toulouse, Toulouse, France
4Department of Biochemistry, Duke University Medical Center, Durham, United States of America
5Center for Human Disease Modeling, Duke University Medical Center, Durham, United States of America
6BGI-Shenzhen, Shenzhen, China
7Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
8UMR 1149 INSERM, Faculté de Médecine Site Bichat, Paris, France
9Service of Medical Genetics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
10Division of Hematology/Oncology, Children's Mercy Hospital and Clinics, Kansas City, United States of America
11Division of Pediatrics, University Hospital Lausanne (CHUV), Lausanne, Switzerland
12Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Paris, France
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Published August 1, 2024 - More info
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 two 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. Furthermore, 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.