Diamond Blackfan Anemia (DBA) is blood disease in which the bone marrow malfunctions and fails to make enough erythrocytes, or red blood cells. Inherited in an autosomal dominant pattern, DBA affects approximately five to seven million infants globally, and about half of the DBA patients possess physical abnormalities, such as microcephaly, hypertelorism, Ptosis, micrognathia, webbed neck, absent thumbs, cataracts, and glaucoma. In addition, affected patients have an increased risk of developing acute myeloid lymphoma.
DBA is mainly caused by mutations in the genes that code for ribosomal proteins. These mutations lead to ribosomal protein haplo-insufficiency, a condition where the ribosomal protein(s) are expressed in statistically significant lower levels compared to normal controls. A major ribosomal protein that is underexpressed in DBA patients is RPS 19. RPS 19 levels decreasing produces many effects downstream, which ultimately result in the phenotypic characteristics of DBA.
Recent studies are exploring the effects of lower RPS 19 levels on NLK activity and consequent phosphorylation downstream. Decreased RPS 19 levels increase NLK activity, which in turn, phosphorylates the mTOR protein and Myb, a transcription factor.
When Myb gets phosphorylated in the erythrocytes of DBA patients, it also gets ubiquinated soon after and thus, sent to the proteosome where it gets degraded. This degradation decreases the levels of Myb, leading to the symptoms of DBA. On the other hand, when the mTOR protein gets phosphorylated, its levels drop and its activity is inhibited. This inhibition causes increased erythrocyte autophagy, which is seen in DBA patients.
Perhaps, if proteosome inhibitor is added into the erythrocyte cell lines cultured from the DBA patients, Myb levels could be rescued to alleviate DBA. Also, if NLK levels in the erythrocyte cell lines cultured from the DBA patients are decreased (brought back to normal), the erythrocyte colony count could increase back to normal levels instead of decreasing via autophagy. Since a low erythrocyte count is a major characteristic of DBA, normalizing the NLK levels in the affected cell lines could help eliminate the problem. These two approaches could be promising in tackling DBA. If proven to work, drugs could be developed to lower NLK levels and to act as a Myb proteosome inhibitor in the patients, thus being of great value in the clinical field.
“Diamond Blackfan Anemia,” Genetics and Rare Diseases Information Center, accessed July 5, 2017, https://rarediseases.info.nih.gov/diseases/6274/diamond-blackfan-anemia.
Idol RA, Robledo S, Du HY, Crimmins DL, Wilson DB, Ladenson JH, Bessler M, Mason PJ, “Cells depleted for RPS19, a protein associated with Diamond Blackfan Anemia, show defects in 18S ribosomal RNA synthesis and small ribosomal subunit production,” PubMed 1 (2007): 35-43, accessed July 5, 2017, doi: 10.1016/j.bcmd.2007.02.001.