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Diamond-Blackfan anemia (DBA) is a rare congenital pure red-cell aplasia with an autosomal dominant inheritance pattern, characterized by normochromic macrocytic anemia and variable congenital anomalies. While heterozygous mutations in the ribosomal protein S19 gene account for approximately 25% of cases, pathogenic variants in other ribosomal protein genes, including RPS24, have been implicated in the disease (PMID:17186470).
In a cohort of RPS19 mutation-negative DBA probands, de novo heterozygous loss-of-function variants in RPS24 were identified in 4 unrelated individuals, representing roughly 2% of cases (PMID:17186470). One recurrent truncating variant, c.46C>T (p.Arg16Ter), was reported, alongside additional frameshift and splice-site mutations that uniformly truncate the RPS24 protein.
All reported RPS24 variants in DBA are predicted or proven to result in premature protein termination, supporting a haploinsufficiency mechanism. No pathogenic missense variants have been described to date, underscoring the critical requirement of full-length RPS24 for ribosomal biogenesis.
Segregation data beyond de novo occurrences are lacking, and no additional affected relatives were reported, consistent with sporadic emergence of RPS24 mutations in most DBA families.
Functional studies in a zebrafish model of RPS24 haploinsufficiency demonstrated impaired erythropoiesis, reduced hemoglobinization, and downregulation of satb1a mediated by disrupted STAT6 signaling, effectively recapitulating key features of human DBA (PMID:40054062).
Collectively, the genetic and experimental evidence supports a moderate clinical validity classification for the association between RPS24 and Diamond-Blackfan anemia. Additional segregation analyses and larger patient cohorts would further refine risk estimates and guide clinical testing. Key take-home: RPS24 loss-of-function variants cause DBA through haploinsufficiency and impaired erythroid differentiation.
Gene–Disease AssociationModerate4 unrelated probands with de novo RPS24 loss-of-function variants ([PMID:17186470]); functional concordance in zebrafish model. Genetic EvidenceModerateDe novo heterozygous truncating RPS24 variants identified in 4 independent DBA probands without segregation. Functional EvidenceModerateZebrafish haploinsufficiency model recapitulates human erythroid defects via STAT6-SATB1 pathway ([PMID:40054062]). |