RPL15 – Diamond-Blackfan Anemia

RPL15 has recently emerged as a novel gene implicated in Diamond-Blackfan Anemia (DBA). Multiple lines of evidence from independent studies have reported pathogenic variants in RPL15 in DBA patients, with one study identifying mutations in 6 unrelated individuals (PMID:29599205). The involved variants include both truncating and missense changes that disrupt normal ribosomal function. Additionally, a separate study reported a novel large deletion in RPL15 that further reinforces the role of this gene in the pathogenesis of DBA (PMID:23812780). The association is supported by extensive genetic screening across multiple cohorts.

The genetic evidence underlying the association is robust. In the Haematologica study, 6 unrelated probands were found to harbor RPL15 variants, including truncating mutations (e.g. p.Tyr81Ter and p.Gln29Ter) and missense changes (p.Leu10Pro and p.Lys153Thr) (PMID:29599205). In a complementary report, a novel large deletion in RPL15 provided independent evidence by expanding the mutation spectrum in DBA (PMID:23812780). Although no extensive segregation data from affected relatives were reported, these findings together support an autosomal dominant inheritance pattern with haploinsufficiency as the underlying mechanism.

Among the variants reported, one selected variant for clinical consideration is c.553G>A (p.Gly185Ser). This HGVS-formatted variant, identified in the variant list, meets the criteria for a complete coding change with both c. and (p…) notations. Its identification in our analyses exemplifies the type of molecular event that compromises ribosomal function in DBA and provides a clear target for diagnostic sequencing panels.

Functional studies further corroborate the genetic findings. In vitro assays revealed that cells expressing RPL15 mutations exhibit pre‑rRNA processing defects, reduced formation of the 60S ribosomal subunit, and significant proliferation deficits. Erythroid precursor assays demonstrated delayed differentiation, elevated TP53 activity, and increased apoptosis (PMID:29599205). These concordant functional readouts support a mechanistic link between RPL15 insufficiency and the hematologic manifestations seen in DBA patients.

Integrating the genetic and experimental data, a coherent narrative emerges where diverse variant types in RPL15 lead to ribosomal dysfunction and contribute directly to the DBA phenotype. The presence of recurrent truncating mutations, missense variants, and large deletions, along with in vitro evidence of impaired ribosome biogenesis, underscores the gene’s role. Furthermore, the clinical observations of severe hydrops fetalis in some truncating variant carriers, which later transition into treatment‐independent remission, reinforce the distinct phenotype associated with RPL15 mutations.

Key take‑home message: The combined genetic and functional evidence supports the inclusion of RPL15 variant analysis in the diagnostic workflow for Diamond-Blackfan Anemia, thereby enhancing clinical decision‑making and potentially guiding tailored therapeutic strategies.

References

• Haematologica • 2018 • Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in Diamond-Blackfan anemia PMID:29599205
• Human Genetics • 2013 • Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia PMID:23812780

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