HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia.

Autor:	O'Donohue MF; MCD, Centre de Biologie Intégrative, Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), UT3, Toulouse, France., Da Costa L; University of Paris Cité, Paris, France.; Hematim EA4666, Amiens, France.; Laboratory of Excellence for Red Cells, LABEX GR-Ex, Paris, France.; Service d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France., Lezzerini M; Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam, The Netherlands., Unal S; Pediatric Hematology Unit, Department of Pediatrics, Medical Faculty, and.; Research Center on Fanconi Anemia and Other Inherited Bone Marrow Failure Syndromes, Hacettepe University, Ankara, Turkey., Joret C; RNA Molecular Biology, Fonds de la Recherche Scientifique (F.R.S./FNRS), Université libre de Bruxelles (ULB), Gosselies, Belgium., Bartels M; Department of Pediatric Hematology and., Brilstra E; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., Scheijde-Vermeulen M; Princess Máxima Center for Pediatric Oncology, Department of Pathology, Utrecht, The Netherlands., Wacheul L; RNA Molecular Biology, Fonds de la Recherche Scientifique (F.R.S./FNRS), Université libre de Bruxelles (ULB), Gosselies, Belgium., De Keersmaecker K; Laboratory for Disease Mechanisms in Cancer, Department of Oncology, Katholieke Universiteit Leuven (KU Leuven) and Leuven Cancer Institute (LKI), Leuven, Belgium., Vereecke S; Laboratory for Disease Mechanisms in Cancer, Department of Oncology, Katholieke Universiteit Leuven (KU Leuven) and Leuven Cancer Institute (LKI), Leuven, Belgium., Labarque V; Department of Pediatric Hemato-Oncology, University Hospitals Leuven, Leuven, Belgium., Saby M; UMR S1134, INSERM, Paris, France., Lefevre SD; Laboratory of Excellence for Red Cells, LABEX GR-Ex, Paris, France.; UMR S1134, INSERM, Paris, France., Platon J; Hematim EA4666, Amiens, France., Montel-Lehry N; MCD, Centre de Biologie Intégrative, Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), UT3, Toulouse, France., Laugero N; UMR 1297-I2MC, INSERM, Université de Toulouse, Toulouse, France., Lacazette E; UMR 1297-I2MC, INSERM, Université de Toulouse, Toulouse, France., van Gassen K; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., Houtkooper RH; Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam, The Netherlands., Simsek-Kiper PO; Pediatric Genetics Unit, Department of Pediatrics, Medical Faculty, Hacettepe University, Ankara, Turkey., Leblanc T; Immuno-Hematology Department, Hôpital Robert-Debré, Assistance Publique-Hôpitaux de Paris, Paris, France.; EA-3518, Université Paris Cité, Paris, France., Yarali N; Pediatric Hematology Unit, Department of Pediatrics, Medical Faculty, Yildirim Beyazit University, Ankara, Turkey; and., Cetinkaya A; Department of Medical Genetics, Medical Faculty, Hacettepe University, Ankara, Turkey., Akarsu NA; Department of Medical Genetics, Medical Faculty, Hacettepe University, Ankara, Turkey., Gleizes PE; MCD, Centre de Biologie Intégrative, Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), UT3, Toulouse, France., Lafontaine DLJ; RNA Molecular Biology, Fonds de la Recherche Scientifique (F.R.S./FNRS), Université libre de Bruxelles (ULB), Gosselies, Belgium., MacInnes AW; Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2022 May 26; Vol. 139 (21), pp. 3111-3126.
DOI:	10.1182/blood.2021011846
Abstrakt:	The congenital bone marrow failure syndrome Diamond-Blackfan anemia (DBA) is typically associated with variants in ribosomal protein (RP) genes impairing erythroid cell development. Here we report multiple individuals with biallelic HEATR3 variants exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability. These variants destabilize a protein whose yeast homolog is known to synchronize the nuclear import of RPs uL5 (RPL11) and uL18 (RPL5), which are both critical for producing ribosomal subunits and for stabilizing the p53 tumor suppressor when ribosome biogenesis is compromised. Expression of HEATR3 variants or repression of HEATR3 expression in primary cells, cell lines of various origins, and yeast models impairs growth, differentiation, pre-ribosomal RNA processing, and ribosomal subunit formation reminiscent of DBA models of large subunit RP gene variants. Consistent with a role of HEATR3 in RP import, HEATR3-depleted cells or patient-derived fibroblasts display reduced nuclear accumulation of uL18. Hematopoietic progenitor cells expressing HEATR3 variants or small-hairpin RNAs knocking down HEATR3 synthesis reveal abnormal acceleration of erythrocyte maturation coupled to severe proliferation defects that are independent of p53 activation. Our study uncovers a new pathophysiological mechanism leading to DBA driven by biallelic HEATR3 variants and the destabilization of a nuclear import protein important for ribosome biogenesis. (© 2022 by The American Society of Hematology.)
Databáze:	MEDLINE
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