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This summary details the association between the ribosomal protein gene RPL18 and Diamond-Blackfan anemia, a rare inherited bone marrow failure syndrome characterized by erythroid hypoplasia and congenital anomalies. The clinical presentation of DBA includes red blood cell aplasia that leads to severe anemia and a predisposition to various malignancies (PMID:28280134). In this context, accurate gene‐disease associations are critical for guiding diagnostic decision‑making and enabling targeted commercial assays.
Genetic evidence indicates that DBA is predominantly transmitted in an autosomal dominant manner, with heterozygous pathogenic variants contributing to the disease phenotype. A multi‑patient study identified a heterozygous missense variant in RPL18 in DBA patients; specifically, the variant c.152T>C (p.Leu51Ser) was observed to disrupt ribosomal function (PMID:28280134). Although segregation data regarding additional affected relatives is limited in the provided reports, the identification of the variant in an independent family adds significant support to the genetic association.
The case series and comprehensive genomic evaluations described in the literature further highlight a robust variant spectrum in ribosomal protein genes among DBA patients. For RPL18, the reported variant, c.152T>C (p.Leu51Ser), is consistent with a deleterious effect on protein function, which is in line with the disruptive changes typically seen in ribosomal abnormalities leading to impaired erythropoiesis. This finding is supported by the fact that pathogenic alterations in ribosomal proteins have been recurrently implicated in DBA (PMID:28280134).
Complementary functional studies offer critical experimental validation for the role of RPL18 in DBA. A zebrafish model featuring rpl18 deficiency was generated using CRISPR/Cas9 technology and demonstrated a marked reduction in mature red blood cells, mirroring the erythroid defects observed in DBA patients (PMID:32075953). Additionally, the study showed that modulation of the JAK2-STAT3 signaling pathway could partially rescue the anemic phenotype, providing mechanistic insight into RPL18-mediated alterations in hematopoiesis.
Integration of the genetic and functional evidence presents a coherent narrative: the heterozygous c.152T>C (p.Leu51Ser) variant in RPL18 is pathogenic and contributes to the clinical phenotype of Diamond-Blackfan anemia. This association is supported by independent multi‑patient studies and validated by in vivo experimental models, emphasizing the potential for incorporating RPL18 variant analysis into routine diagnostic workflows for DBA.
Key take‑home: The compelling convergence of genetic and functional data on RPL18 underscores its clinical utility as a diagnostic marker for Diamond-Blackfan anemia, facilitating improved patient management and tailored therapeutic strategies.
Gene–Disease AssociationStrongThe identification of a heterozygous missense variant in RPL18 in a DBA patient from an independent study (PMID:28280134) and its functional recapitulation in a zebrafish model (PMID:32075953) provides convergent evidence supporting a strong gene-disease association. Genetic EvidenceModerateThe presence of the c.152T>C (p.Leu51Ser) variant in RPL18 in affected individuals, along with its recurrence among DBA cases, underpins moderate genetic evidence for pathogenicity. Functional EvidenceStrongIn vivo studies using a zebrafish model have demonstrated that rpl18 deficiency leads to erythroid maturation defects that mimic DBA, with rescue experiments further reinforcing its functional role in disease pathogenesis. |