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

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

  • Blood. 2022 May 26;139(21):3111-3126. doi: 10.1182/blood.2021011846.
Marie-Françoise O'Donohue 1,  Lydie Da Costa 2 3 4 5,  Marco Lezzerini 6,  Sule Unal 7 8,  Clément Joret 9,  Marije Bartels 10,  Eva Brilstra 11,  Marijn Scheijde-Vermeulen 12,  Ludivine Wacheul 9,  Kim De Keersmaecker 13,  Stijn Vereecke 13,  Veerle Labarque 14,  Manon Saby 15,  Sophie D Lefevre 4 15,  Jessica Platon 3,  Nathalie Montel-Lehry 1,  Nathalie Laugero 16,  Eric Lacazette 16,  Koen van Gassen 11,  Riekelt H Houtkooper 6,  Pelin Ozlem Simsek-Kiper 17,  Thierry Leblanc 18 19,  Nese Yarali 20,  Arda Cetinkaya 21,  Nurten A Akarsu 21,  Pierre-Emmanuel Gleizes 1,  Denis L J Lafontaine 9,  Alyson W MacInnes 6
Affiliations

Affiliations

  • 1 MCD, Centre de Biologie Intégrative, Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), UT3, Toulouse, France.
  • 2 University of Paris Cité, Paris, France.
  • 3 Hematim EA4666, Amiens, France.
  • 4 Laboratory of Excellence for Red Cells, LABEX GR-Ex, Paris, France.
  • 5 Service d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France.
  • 6 Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam, The Netherlands.
  • 7 Pediatric Hematology Unit, Department of Pediatrics, Medical Faculty, and.
  • 8 Research Center on Fanconi Anemia and Other Inherited Bone Marrow Failure Syndromes, Hacettepe University, Ankara, Turkey.
  • 9 RNA Molecular Biology, Fonds de la Recherche Scientifique (F.R.S./FNRS), Université libre de Bruxelles (ULB), Gosselies, Belgium.
  • 10 Department of Pediatric Hematology and.
  • 11 Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 12 Princess Máxima Center for Pediatric Oncology, Department of Pathology, Utrecht, The Netherlands.
  • 13 Laboratory for Disease Mechanisms in Cancer, Department of Oncology, Katholieke Universiteit Leuven (KU Leuven) and Leuven Cancer Institute (LKI), Leuven, Belgium.
  • 14 Department of Pediatric Hemato-Oncology, University Hospitals Leuven, Leuven, Belgium.
  • 15 UMR S1134, INSERM, Paris, France.
  • 16 UMR 1297-I2MC, INSERM, Université de Toulouse, Toulouse, France.
  • 17 Pediatric Genetics Unit, Department of Pediatrics, Medical Faculty, Hacettepe University, Ankara, Turkey.
  • 18 Immuno-Hematology Department, Hôpital Robert-Debré, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • 19 EA-3518, Université Paris Cité, Paris, France.
  • 20 Pediatric Hematology Unit, Department of Pediatrics, Medical Faculty, Yildirim Beyazit University, Ankara, Turkey; and.
  • 21 Department of Medical Genetics, Medical Faculty, Hacettepe University, Ankara, Turkey.
PMID: 35213692 DOI: 10.1182/blood.2021011846
Abstract

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.

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