The syndrome of congenital bone marrow failure Diamond-Blackfan anemia (DBA) is often linked with ribosomal protein (RP) gene polymorphisms that impede erythroid cell development. For a study, researchers described many people with biallelic HEATR3 mutations, bone marrow failure, small height, facial and acromelic dysmorphic traits, and cerebral handicap. 

When ribosome biogenesis is disrupted, these variations destabilize a protein whose yeast homolog is known to coordinate the nuclear import of RPs uL5 (RPL11) and uL18 (RPL5), which are both crucial for generating ribosomal subunits and maintaining the p53 tumor suppressor. HEATR3 variation expression or suppression hampers growth, differentiation, pre-ribosomal RNA processing, and ribosomal subunit production in primary cells, cell lines of diverse sources, and yeast models, similar to DBA models of large subunit RP gene variants. 

HEATR3-depleted cells or patient-derived fibroblasts showed lower nucleus accumulation of uL18, which is consistent with a function for HEATR3 in RP import. In addition, hematopoietic progenitor cells harboring HEATR3 mutations or small-hairpin RNAs inhibiting HEATR3 synthesis showed aberrant erythrocyte maturation accompanied by severe proliferation abnormalities independent of p53 activation. The findings revealed a novel pathogenic mechanism involving biallelic HEATR3 variations and the instability of a nuclear import protein required for ribosome synthesis.

Reference:ashpublications.org/blood/article/139/21/3111/484180/HEATR3-variants-impair-nuclear-import-of-uL18-RPL5