Diamond-Blackfan anemia and nucleolar transport

Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia characterized by pure red blood cell aplasia and congenital abnormalities. Curiously, 25% of individuals with DBA carry one mutant allele of the RPS19 gene. RPS19 is a protein subunit of the ribosome, and ribosomes are assembled in the nucleus, more specifically in the nucleolus, of eukaryotic cells. How RPS19 deficiency affects ribosome assembly or results in the developmental defects of DBA remains unknown.

In this issue, Da Costa and coworkers (page 5039) explore the subcellular localization of the RPS19 protein and the effects of mutations on this localization. RPS19 was detected in the nucleoli of transfected mammalian cells. Structure-function analysis revealed two nucleolar localization signals (NoSs) in RPS19. Interestingly, 2 DBA patient–derived mutations, each of which localized to 1 of the 2 NoSs, resulted in a failure of targeting RPS19 to the nucleolus.

This study provides the first link between DBA patient–derived mutations in RPS19 and mislocalization and misexpression of the RPS19 protein. The study also adds to the growing list of protein-targeting signals that direct subnuclear architecture. Perhaps most important, the paper helps to frame the future of research in the DBA field. It now becomes important to determine whether misexpression of RPS19 affects ribosome assembly, erythroblast maturation, or even the steroid responsiveness of DBA bone marrow cells.