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Diamond-Blackfan anemia (DBA) is a rare inherited disorder characterized by red blood cell aplasia and a range of congenital anomalies. Recent studies have implicated RPS29 (HGNC:10419) as a causative gene in DBA, expanding the spectrum of ribosomal protein genes involved in this condition (PMID:24829207).
In one study, whole‑exome sequencing in a large DBA family identified a single nonsynonymous mutation that co‐segregated with disease. All five affected individuals harbored the RPS29 variant, c.91A>T (p.Ile31Phe), whereas the unaffected noncarrier parent did not carry the mutation (PMID:24829207). An independent DBA family was found to carry a distinct RPS29 missense mutation (p.Ile50Thr), further corroborating the gene‑disease link.
The genetic evidence is compelling with two independent families showing rare, deleterious missense variants in RPS29. Segregation analysis within families, with five affected individuals in one family and additional supporting cases in another, reinforces the association between RPS29 mutations and DBA. This pattern of inheritance is consistent with an autosomal dominant mechanism involving haploinsufficiency (PMID:24829207).
Functional studies have provided additional support for the role of RPS29 in DBA. In a zebrafish model, rps29 mutants recapitulated the hematopoietic defects characteristic of DBA, including reduced red blood cell production and increased apoptosis. Notably, genetic disruption of p53 nearly completely rescued these phenotypes, demonstrating a clear mechanistic link between RPS29 haploinsufficiency and the DBA phenotype (PMID:22120640).
Integrating both the genetic and functional evidence provides a robust narrative for the pathogenicity of RPS29 mutations in Diamond‑Blackfan anemia. The identification of distinct, pathogenic variants combined with segregation data and in vivo rescue experiments underscores the gene’s clinical relevance in DBA diagnosis and management (PMID:30503522).
Key take‑home sentence: The strong association between RPS29 mutations and Diamond‑Blackfan anemia is clinically actionable, offering definitive insights for diagnostic decision‑making, commercial test development, and future research publications.
Gene–Disease AssociationStrongRPS29 mutations were identified in two independent DBA families, with five affected individuals in one family and a distinct missense variant in another, supported by clear segregation and corroborative phenotype data (PMID:24829207, PMID:30503522). Genetic EvidenceStrongTwo distinct missense variants, including c.91A>T (p.Ile31Phe), have been found in DBA patients. These variants co‐segregate with the disease in affected family members, confirming a deleterious effect and supporting autosomal dominant inheritance (PMID:24829207). Functional EvidenceStrongFunctional assays in a zebrafish model demonstrated that rps29 mutations recapitulate hematopoietic defects typical of DBA. Rescue experiments via p53 disruption further validate the causal link between RPS29 haploinsufficiency and the disease phenotype (PMID:22120640). |