RPS17 and Diamond-Blackfan Anemia

Multiple independent studies have established a robust association between variants in RPS17 and Diamond-Blackfan anemia (DBA), a congenital bone marrow failure syndrome primarily characterized by pure red cell aplasia (PMID:19953637, PMID:17647292). The genetic evidence comprises case reports and multi‐patient studies that have identified recurrent, pathogenic variants affecting the initiation codon of RPS17. Notably, the novel variant c.1A>G (p.Met1Val) was reported in a Korean patient with DBA, representing the third such case described in the literature (PMID:19953637).

Further supporting the genetic association, additional studies have identified de novo mutations and copy-number deletions in RPS17 across unrelated probands, with segregation analyses in some cases demonstrating that affected relatives carry the variant, thereby reinforcing the autosomal dominant pattern of inheritance observed in DBA (PMID:17647292, PMID:38002903).

The genetic evidence is bolstered by functional studies: disruption of RPS17 in bacterial models leads to defects in ribosome assembly and the generation of aberrant ribosomal subunits (PMID:10561594). In zebrafish models, knockdown of rps17 resulted in impaired erythropoiesis and reduced expression of genes critical for red blood cell stability, further corroborating the mechanistic link between RPS17 haploinsufficiency and the DBA phenotype (PMID:40015014).

Multi‐patient studies have also shown that a subset of DBA cases can be attributed to RPS17 mutations. These studies, which include assessments of splice variants and gene deletions, indicate that RPS17 is part of a broader network of ribosomal proteins whose deficiency disrupts normal erythroid development (PMID:22262766).

Collectively, the integration of robust genetic findings and supportive experimental data supports a ClinGen classification of Strong for the association between RPS17 and Diamond-Blackfan anemia. This association not only enhances diagnostic decision-making but also provides a framework for commercial genetic assay development and informs future research into targeted therapeutics.

Key Take‑home sentence: The convergence of multi‑case genetic findings and functional assays decisively supports the clinical utility of screening RPS17 variants in DBA diagnostics.

References

• Pediatric blood & cancer • 2010 • A novel initiation codon mutation in the ribosomal protein S17 gene in a patient with Diamond-Blackfan anemia PMID:19953637
• Human mutation • 2007 • Ribosomal protein S17 gene (RPS17) is mutated in Diamond-Blackfan anemia PMID:17647292
• Children (Basel, Switzerland) • 2023 • The Diverse Genomic Landscape of Diamond-Blackfan Anemia: Two Novel Variants and a Mini-Review PMID:38002903
• Blood • 2011 • Ribosomal protein gene deletions in Diamond-Blackfan anemia PMID:22045982
• European journal of biochemistry • 1999 • Ribosomal gene disruption in the extreme thermophile Thermus thermophilus HB8. Generation of a mutant lacking ribosomal protein S17 PMID:10561594
• Blood cells, molecules & diseases • 2025 • Unveiling the role of RPS17 and SLC4A1 in Diamond-Blackfan Anemia: A zebrafish-based study PMID:40015014

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