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Published January 1, 2022 | Version v1
Journal article Open

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

Creators

  • 1. Univ Toulouse, CNRS, UT3, Ctr Biol Integrat,MCD, Toulouse, UT, France
  • 2. Univ Amsterdam, Lab Genet Metab Dis, Amsterdam MC, Amsterdam Gastroenterol Endocrinol & Metab, Amsterdam, Netherlands
  • 3. Univ Libre Bruxelles ULB, RNA Mol Biol, Fonds Rech Sci FRS FNRS, Gosselies, Belgium
  • 4. Univ Med Ctr Utrecht, Dept Pediat Hematol, Utrecht, Netherlands
  • 5. Univ Med Ctr Utrecht, Dept Genet, Utrecht, Netherlands
  • 6. Princess Maxima Ctr Pediat Oncol, Dept Pathol, Utrecht, Netherlands
  • 7. Univ Hosp Leuven, Dept Pediat Hematooncol, Leuven, Belgium
  • 8. INSERM, UMR 51134, Paris, France
  • 9. Hematim EA4666, Amiens, France
  • 10. Univ Toulouse, INSERM, UMR 1297 I2MC, Toulouse, France

Description

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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