Connecting ribosomes with bone marrow failure

The SBDS protein, defective in Schwachman-Diamond syndrome (SDS), associates with the 60S ribosomal subunit and the 28S ribosomal RNA; mutations in SBDS most likely cause abnormal ribosomal biogenesis.

The identification of mutations in the ribosomal protein S19 (RPS19) gene as the cause of Diamond-Blackfan anemia (DBA)¹  was met with surprise because it was not expected that a defective protein with a generic function would generate a rather specific phenotype in the form of anemia due to bone marrow failure (reviewed in Flygare and Karlsson² ). Now, almost a decade later, convincing evidence is accumulating that the cause of the anemia in DBA is due to abnormal ribosomal function and not due to nonribosomal effects mediated by RPS19. Two groups have independently reported that mutations in RPS19 cause abnormal processing of ribosomal RNA, leading to abnormalities in ribosomal function.^3,4  Further support for abnormal ribosomal function in DBA was provided recently by the identification of mutations in RPS24 in a few DBA patients.⁵  In addition to DBA, ribosomal dysfunction has been implicated in several other inherited bone marrow failure syndromes, for example SDS, dyskeratosis, and congenital and cartilage-hair hypoplasia.⁶ 

In this issue of Blood, Ganapathi and colleagues investigate the role of the SBDS protein in SDS, an autosomal recessive disorder characterized by bone marrow failure, exocrine pancreas dysfunction, and leukemia predisposition. Their findings show that SBDS is associated with the large 60S ribosomal precursor subunit and 28S ribosomal RNA, but it is not found in mature ribosomes. SBDS forms a complex with nucleophosmin, a multifunctional protein implicated in ribosome biogenesis and leukemogenesis. However, no block was detected in ribosomal RNA processing, and the relative amounts of the 40S, 60S, and 80S ribosomal subunits were unaffected in cells producing low amounts of SBDS after transfection of siRNA against SBDS. Similar experiments were done with fibroblasts from SDS patients without detecting abnormalities in the processing of ribosomal RNA or abnormal ratios between the different ribosomal subunits.

In RPS19-deficient DBA, abnormal processing of 18S ribosomal RNA is seen, and there is diminished 40S ribosomal subunit production.^3,4  Therefore, the molecular mechanism that leads to bone marrow failure in RPS19-deficient DBA is distinct from the mechanism in SBDS-deficient SDS. Although the precise molecular mechanism in SBDS-deficient SDS is not fully understood, it seems that this deficiency disturbs the biogenesis of 60S ribosomal subunits without affecting ribosomal RNA processing. The findings of Ganapathi and colleagues demonstrate, once again, that defects in ribosomal biogenesis or ribosomal function can cause underproduction of specific lineages within the hematopoietic system. More detailed studies need to be performed to understand fully the molecular mechanism in these bone marrow failure syndromes in order to allow future development of specific pharmacologic therapies for these disorders.