Abstract
Diamond-Blackfan Anemia (DBA) is an inherited rare disease characterized with severe pure red cell aplasia, and it is caused by the defective ribosome biogenesis stemming from the impairment of ribosomal proteins. Among all DBA-associated ribosomal proteins, RPS19 affects most patients and carries most DBA mutations. Revealing how these mutations lead to the impairment of RPS19 is highly demanded for understanding the pathogenesis of DBA, but a systematic study is currently lacking. In this work, based on the complex structure of human ribosome, we comprehensively studied the structural basis of DBA mutations of RPS19 by using computational methods. Main structure elements and five conserved surface patches involved in RPS19-18S rRNA interaction were identified. We further revealed that DBA mutations would destabilize RPS19 through disrupting the hydrophobic core or breaking the helix, or perturb the RPS19-18S rRNA interaction through destroying hydrogen bonds, introducing steric hindrance effect, or altering surface electrostatic property at the interface. Moreover, we trained a machine-learning model to predict the pathogenicity of all possible RPS19 mutations. Our work has laid a foundation for revealing the pathogenesis of DBA from the structural perspective.
Highlights
Diamond-Blackfan Anemia (DBA, OMIM # 105650) is an inherited rare pure red blood cell aplasia (∼5 to 7 per million birth) (Vlachos et al, 2001; Da Costa et al, 2018) characterized by the failure of erythropoiesis but with normal production of leukocytes and platelets in the bone marrow (Diamond, 1938; Ball, 2011; Da Costa et al, 2018; Engidaye et al, 2019)
An in-depth understanding of structure is the basis of studying mutations in a structural context, so we investigated the structure of human RPS19 in detail
We conducted a systematic study aiming at revealing the structural basis of DBA mutations at RPS19
Summary
Diamond-Blackfan Anemia (DBA, OMIM # 105650) is an inherited rare pure red blood cell aplasia (∼5 to 7 per million birth) (Vlachos et al, 2001; Da Costa et al, 2018) characterized by the failure of erythropoiesis but with normal production of leukocytes and platelets in the bone marrow (Diamond, 1938; Ball, 2011; Da Costa et al, 2018; Engidaye et al, 2019). It usually presents during the first year of life, and affects the follow-up growth and development, resulting in short stature and congenital abnormalities. The impaired ribosome biogenesis will lead to decreased ribosome quantity and the failure of erythropoiesis (Engidaye et al, 2019; Ulirsch et al, 2019)
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