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

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 ribosomal proteins 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-rRNA 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.

Mapping the landscape of genetic dependencies in chordoma

“…Collectively, the dependency genes identified herein can be classified into a broad range of biological functions. Canonical roles for these genes include: differentiation and development (the developmental transcription factors TBXT, SOX9, and ZEB2); proliferative signaling (PTPN11 and EGFR); environmental sensing and metabolism (the aryl hydrocarbon receptor AHR and its transcription partner ARNT, the glucose transporter SLC2A1, the amino-acid transporter SLC7A5, the cAMP signaling regulatory component PRKAR1A, and the cholesterol metabolism regulator UBIAD1); cell-cycle progression (the cell cycle cyclin-dependent kinase CDK6, a cell-cycle gene regulator THAP1, and regulator of cell-cycle checkpoint activation and DNA replication DSCC1) 51,52 ; immune regulation (ADAR, PRKRA, PTPN11, and a suppressor of the innate immune system OTUD5); RNA splicing (the U1 snRNP subunit gene LUC7L2, and a pre-mRNA splicing co-activator SRRM2) 53 ; cellular transport (SLC2A1, SLC7A5, the ribosomal protein transportrelated gene HEATR3, and a regulator of endoplasmic reticulum and secretory function IER3IP1) 54,55 ; and DNA replication and repair (the Fanconi anemia core complex component FANCM, and DSCC1) (Fig. 6).…”

Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia

“…The mutations were found at a splice donor site of the GATA1 gene, and this leading to the impaired production of the full-length form of the protein, which required for normal erythropoiesis in humans [ 17 , 36 ]. In addition, 2 RP chaperones, TSR2 [ 37 ] and HEATR3 [ 38 ], have also been identified in DBA patients. The ribosomal assembly factor TSR2 , which is an RPS26 chaperone (X-chromosomal gene encoding a direct binding partner of RPS26 ), has a critical role in ensuring adequate ribosome levels in hematopoietic progenitors [ 39 ].…”

Mapping the landscape of genetic dependencies in chordoma

“…Collectively, the dependency genes identified herein can be classified into a broad range of biological functions. Canonical roles for these genes include: differentiation and development (the developmental transcription factors TBXT, SOX9 , and ZEB2 ); proliferative signaling ( PTPN11 and EGFR ); environmental sensing and metabolism (the aryl hydrocarbon receptor AHR and its transcription partner ARNT , the glucose transporter SLC2A1 , the amino-acid transporter SLC7A5 , the cAMP signaling regulatory component PRKAR1A , and the cholesterol metabolism regulator UBIAD1 ); cell-cycle progression (the cell cycle cyclin-dependent kinase CDK6 , a cell-cycle gene regulator THAP1 , and regulator of cell-cycle checkpoint activation and DNA replication DSCC1 ) 48,49 ; immune regulation ( ADAR, PRKRA, PTPN11 , and a suppressor of the innate immune system OTUD5 ); RNA splicing (the U1 snRNP subunit gene LUC7L2 , and a pre-mRNA splicing co-activator SRRM2 ) 50 ; cellular transport ( SLC2A1, SLC7A5 , the ribosomal protein transport-related gene HEATR3 , and a regulator of endoplasmic reticulum and secretory function IER3IP1 ) 51,52 ; and DNA replication and repair (the Fanconi anemia core complex component FANCM , and DSCC1 ) ( Figure 6 ).…”