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Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia marked by macrocytic anemia, reticulocytopenia, and a spectrum of congenital anomalies. Heterozygous mutations in RPL11 account for approximately 5%–10% of DBA cases and follow an autosomal dominant inheritance with incomplete penetrance and variable expressivity. Loss-of-function (LoF) variants—including nonsense, frameshift, and splice-site mutations—lead to RPL11 haploinsufficiency, impairing ribosome biogenesis and triggering p53-mediated apoptosis in erythroid progenitors.
Clinically, RPL11-associated DBA presents with early-onset anemia often accompanied by thumb abnormalities, craniofacial defects, cardiac septal defects, and short stature. Multiple cohorts totaling over 200 unrelated probands have been reported across diverse populations, with segregation of pathogenic variants in more than 50 families demonstrating co-segregation with disease features (PMID:19061985, PMID:19191325). The recurrent intronic splice-site mutation c.396+3A>G, as well as truncating variants like c.121G>T (p.Glu41Ter), are among the most frequently observed in affected individuals.
Genetic evidence is robust, with RPL11 variants identified in >100 probands by targeted and exome sequencing studies. Familial and de novo occurrences of frameshift (e.g., c.465_475dup (p.Lys159fsTer)) and nonsense mutations reach the ClinGen genetic cap, supporting a strong association of haploinsufficiency with DBA pathogenesis (PMID:30503522, PMID:31855845). Segregation analyses across multiple multiplex families corroborate autosomal dominant transmission with incomplete penetrance.
Functional studies in zebrafish and mouse models confirm that RPL11 haploinsufficiency recapitulates key DBA features. Rpl11-deficient zebrafish exhibit defective hematopoietic stem cell formation, reduced globin translation, and p53 activation, all reversible by p53 knockdown or L-leucine supplementation (PMID:24341334, PMID:25058426). Conditional Rpl11-haploinsufficient mice develop acute anemia due to p53-dependent erythroid precursor arrest, which is rescued by p53 reduction or disruption of the RPL11–MDM2 interaction (PMID:36435197). These data establish a haploinsufficiency mechanism driving DBA via the RP-MDM2-p53 axis.
No credible conflicting evidence has emerged disputing RPL11’s role in DBA. Alternative phenotypes associated with noncanonical variants remain rare and have not weakened the core association.
In summary, genetic and experimental data conclusively establish that heterozygous LoF variants in RPL11 cause autosomal dominant Diamond-Blackfan anemia through a haploinsufficiency mechanism engaging p53-mediated erythroid failure. Routine screening of RPL11 should be included in DBA gene panels, especially in patients with congenital malformations and atypical presentations.
Gene–Disease AssociationDefinitiveOver 200 unrelated probands across >50 families; consistent segregation and haploinsufficiency mechanism with functional concordance Genetic EvidenceStrongMultiple LoF and splice variants identified in >100 probands, including familial and de novo occurrences reaching ClinGen cap Functional EvidenceModerateRPL11 haploinsufficiency models in zebrafish and mice recapitulate anemia via p53 activation with rescue via p53 reduction |