4.7 Article

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

Journal

BLOOD
Volume 139, Issue 21, Pages 3111-3126

Publisher

AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021011846

Keywords

-

Categories

Funding

  1. ZonMW in the Netherlands [40-44000-98-1008]
  2. TUBITAK in Turkey [315S192, 319S062]
  3. European Union's Horizon 2020 research and innovation programme under the EJP RD COFUND-EJP [825575]
  4. EJP RD/JTC2019/PINT-MULTI in Belgium [R.8015.19]
  5. PDR grant in Belgium [T.0144.20]
  6. Laboratory of Excellence for Red Cells [(LABEX GR-Ex)-ANR Avenir [11-LABX-0005-02]
  7. French National PHRC OFABD
  8. Belgian Fonds de la Recherche Scientifique (F.R.S./FNRS)
  9. Universite Libre de Bruxelles (ULB)
  10. Region Wallonne (SPW EER) (RIBOcancer FSO grant) [1810070]
  11. Fonds Jean Brachet
  12. Internationale Brachet Stiftung
  13. Epitran COST action [CA16120]
  14. Foundation against Cancer [P2016-081, 2016-112]
  15. FWO [1S49817N]
  16. Region Wallonne (SPW EER) (POC grant) [1880014]
  17. ANR-2015-AAP generique-CE12 (DBA-Multigenes)
  18. [ANR-15-RAR3-0007-04]
  19. [ANR-19-RAR4-0016]
  20. [ANR-19-RAR4-0016-02]

Ask authors/readers for more resources

The study reports that individuals with biallelic HEATR3 variants exhibit bone marrow failure, short stature, dysmorphic features, and intellectual disability, similar to Diamond-Blackfan anemia. These variants destabilize a protein important for nuclear import, impacting ribosomal subunit formation and p53 tumor suppressor stabilization.
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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available