RPL26 – Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is an autosomal dominant congenital pure red cell aplasia characterized by normochromic macrocytic anemia, reticulocytopenia (HP:0001896), growth delay (HP:0001510), and congenital malformations in approximately 30–50% of patients (PMID:22431104). RPL26 encodes the ribosomal protein uL24, a component of the 60S large ribosomal subunit, and haploinsufficiency of RPL26 impairs ribosome biogenesis and erythroid differentiation.

Genetic evidence for RPL26 in DBA includes a de novo two-nucleotide deletion, c.120_121del (p.Lys41fs), identified in one of 96 DBA probands screened across 16 RP genes, which co-occurs with severe physical abnormalities and a specific pre-rRNA processing defect affecting both ribosomal subunits (PMID:22431104). Additionally, a familial RPL26 frameshift variant segregates in a father and son presenting with limb malformations without overt anemia; reduced RPL26 protein levels and elevated erythrocyte adenosine deaminase activity were documented in the proband’s lymphoblasts (PMID:39710607).

Only heterozygous loss-of-function RPL26 variants have been reported to date, with no recurrent or founder alleles described. The primary coding variant, c.120_121del (p.Lys41fs), exemplifies the frameshift class leading to premature truncation and likely nonsense-mediated decay. Segregation in one additional affected relative (the proband’s brother) supports pathogenicity, although family size remains limited.

Functional studies demonstrate that RPL26 haploinsufficiency disrupts ribosome biogenesis: patient-derived cells bearing c.120_121del exhibit impaired cleavage of internal transcribed spacers and defective maturation of 40S and 60S subunits, consistent with a large subunit deficit (PMID:22431104). In primary B-cell polysome profiling, carriers of RPL26 variants show reduced 60S and 80S fractions compared to unaffected individuals, corroborating ribosomal assembly defects underlying DBA pathogenesis (PMID:33122585).

No studies to date have refuted the RPL26-DBA association, and experimental concordance between rRNA processing assays and polysome profiling solidifies haploinsufficiency as the mechanism of pathogenicity. Additional genetic or biochemical evidence (e.g., in vivo models, rescue experiments) is anticipated to further clarify disease penetrance and phenotypic variability.

Key Take-home: Heterozygous frameshift variants in RPL26 cause autosomal dominant Diamond-Blackfan anemia via haploinsufficiency, producing characteristic ribosome biogenesis defects; genetic testing for RPL26 should be considered in patients with DBA features, even in the absence of classical hematological findings.

References

• Human Mutation • 2012 • Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond-blackfan anemia. PMID:22431104
• American Journal of Medical Genetics Part A • 2024 • Familial RPL26 Variant Causing Congenital Anomalies Without Hematological Features of Diamond Blackfan Anemia. PMID:39710607
• Journal of Pediatric Hematology/Oncology • 2021 • The Use of B-Cell Polysome Profiling to Validate Novel RPL5 (uL18) and RPL26 (uL24) Variants in Diamond-Blackfan Anemia. PMID:33122585

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