Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by hypoproliferative macrocytic anemia, reticulocytopenia, and congenital malformations (MONDO:0015253). Heterozygous pathogenic variants in ribosomal protein genes impair ribosome biogenesis and cause erythroid aplasia. RPS10 encodes ribosomal protein S10, a component of the 40S subunit critical for pre‐rRNA processing.
Genetic screening of 117 unrelated DBA probands identified three distinct RPS10 mutations in five patients, including frameshift, splice-site, and initiation variants (PMID:20116044). A subsequent Japanese case report described the first East Asian patient harboring a novel initiation codon variant in RPS10 (PMID:22510774). In a Russian cohort, targeted sequencing of 57 patients and relatives uncovered three further RPS10 mutations in independent families (PMID:25946618).
To date, at least nine unrelated probands with RPS10 variants have been reported, encompassing frameshift (e.g., c.260dup (p.Glu88fs)), splice-site, and start-loss mutations. All variants are predicted or shown to lead to loss of function, consistent with an autosomal dominant haploinsufficiency mechanism.
Functional assays demonstrate accumulation of 18S-E pre-rRNA in lymphoblastoid cells from RPS10-mutant patients and recapitulation of this defect upon siRNA-mediated RPS10 knockdown in HeLa cells, confirming impaired 40S subunit maturation (PMID:20116044). These findings align with the erythroid-specific phenotype observed in DBA.
No conflicting reports have challenged the RPS10–DBA association. Together, genetic and experimental data establish RPS10 haploinsufficiency as a definitive cause of DBA. Screening for RPS10 variants should be included in diagnostic panels for early-onset anemia and congenital anomalies.
Key Take-home: RPS10 loss-of-function mutations cause autosomal dominant DBA via defective pre-rRNA processing, supporting its inclusion in diagnostic and carrier screening.
Gene–Disease AssociationDefinitiveNine unrelated probands across three cohorts with consistent AD inheritance and concordant functional data Genetic EvidenceStrongNine probands with RPS10 loss-of-function variants (frameshift, splice and initiation mutations) across three studies reached the genetic evidence cap Functional EvidenceModeratePre-rRNA processing defects in patient cells and siRNA knockdown in HeLa cells confirm haploinsufficiency ([PMID:20116044]) |