Non-Diamond Blackfan anemia disorders of ribosome function: Shwachman Diamond syndrome and 5q- syndrome

Abstract

A number of human disorders, dubbed ribosomopathies, are linked to impaired ribosome biogenesis or function. These include but are not limited to Diamond Blackfan anemia (DBA), Shwachman Diamond syndrome (SDS), and the 5q- myelodysplastic syndrome (MDS). This review focuses on the latter two non-DBA disorders of ribosome function. Both SDS and 5q- syndrome lead to impaired hematopoiesis and a predisposition to leukemia. SDS, due to bi-allelic mutations of the SBDS gene, is a multi-system disorder that also includes bony abnormalities, and pancreatic and neurocognitive dysfunction. SBDS associates with the 60S subunit in human cells and has a role in subunit joining and translational activation in yeast models. In contrast, 5q- syndrome is associated with acquired haplo-insufficiency of RPS14, a component of the small 40S subunit. RPS14 is critical for 40S assembly in yeast models, and depletion of RPS14 in human CD34(+) cells is sufficient to recapitulate the 5q- erythroid defect. Both SDS and the 5q- syndrome represent important models of ribosome function and may inform future treatment strategies for the ribosomopathies.

Fig. 1. Gene products from the ribosomopathies and their putative roles in the ribosome biogenesis pathway

Figure modified from Narla and Ebert, Blood 2010, with permission.

Fig. 2. Two different 5q- interstitial deletions

Interphase FISH shows that in each patient, EGR1 (red) locus from 5q31 chromosomal segment was deleted, while the control probe (green) signal from D5S23 segment hybridizing to 5p15.2 region was present in disomy. Figure courtesy of Prof. Vesna Najfeld, Mount Sinai Medical Center, New York, NY.

Fig. 3. Venn diagram of disorders affecting ribosome function

The non-DBA disorders Shwachman Diamond syndrome (SDS) and 5q- syndrome have overlapping features with DBA. Both SDS and DBA can be associated with impairment of 60S maturation. SBDS may also specifically affect 40S/60S subunit joining. SBDS is also recognized as a multi-functional protein with non-ribosome actions. 5q- syndrome and DBA can both have impaired 40S subunit maturation. However, 5q- syndrome is an acquired haploinsufficiency of RPS14, while DBA may be associated with inherited mutations of either 40S or 60S ribosomal proteins. SDS, DBA and 5q- syndrome all share in common impaired hematopoiesis, which is a manifestation of many of the ribosomopathies.