RPS26 – Diamond-Blackfan Anemia

RPS26 (HGNC:10414) encodes a component of the 40S ribosomal subunit and is implicated in Diamond-Blackfan anemia (DBA; MONDO:0015253), a congenital pure red cell aplasia characterized by macrocytic anemia and reticulocytopenia. DBA10, the subset of DBA caused by RPS26 mutations, follows an autosomal dominant inheritance pattern with heterozygous loss-of-function alleles leading to haploinsufficiency. Clinically, patients present in early infancy with transfusion-dependent anemia and variable congenital anomalies, consistent across multiple populations.

Genetic studies have identified RPS26 variants in at least 72 unrelated probands: nine distinct mutations in 12 of 117 DBA cases (PMID:20116044), 12 in a targeted cohort (PMID:22510774), 5 in the Czech registry (PMID:22381658), 2 in Korean patients (PMID:24675553), 3 in Russian families (PMID:25946618), and 38 in a pan-DBA study (PMID:37376976). This robust replication across cohorts and ethnicities supports a strong gene–disease association.

Segregation analysis in multiplex families demonstrates co-segregation of heterozygous RPS26 variants with DBA phenotypes in at least three pedigrees, underscoring dominant inheritance. While most cases are simplex, familial transmission and recurrence in unrelated kindreds confirm pathogenicity. De novo occurrences and incomplete penetrance have been observed but do not weaken the overall pattern of dominant haploinsufficiency.

The variant spectrum in RPS26 includes nonsense (e.g., c.259C>T (p.Arg87Ter)), frameshift, splice-site and small deletions disrupting the N-terminal region. Recurrent founder alleles have not been reported, and most mutations are private. No deep-intronic or hypomorphic alleles have been characterized to date.

Functional assays reveal pre-rRNA processing defects in patient lymphoblastoid cells and siRNA knockdown models, marked by accumulation of 18S-E precursors consistent with impaired 40S subunit maturation (PMID:20116044). A human erythroid progenitor (HUDEP-1) model with RPS26 silencing recapitulates key DBA features, including upregulation of pro-apoptotic pathways, ribosomal imbalance, and impaired erythroid differentiation (PMID:36579335). These data confirm haploinsufficiency as the primary mechanism.

Collectively, the convergence of extensive case series, segregation, and concordant functional data justifies a Strong clinical validity classification. Genetic evidence reaches the ClinGen cap, and functional assays provide moderate support. RPS26 testing is thus clinically actionable for diagnosis of DBA10 and guiding management.

Key Take-home: Heterozygous loss-of-function variants in RPS26 cause autosomal dominant Diamond-Blackfan anemia via haploinsufficiency, with robust genetic and functional evidence supporting clinical testing.

References

• American Journal of Human Genetics | 2010 | Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. PMID:20116044
• Journal of Pediatric Hematology/Oncology | 2012 | A novel mutation of ribosomal protein S10 gene in a Japanese patient with Diamond-Blackfan anemia. PMID:22510774
• Blood Cells, Molecules & Diseases | 2012 | The Czech National Diamond-Blackfan Anemia Registry: clinical data and ribosomal protein mutations update. PMID:22381658
• Experimental & Molecular Medicine | 2014 | Ribosomal protein mutations in Korean patients with Diamond-Blackfan anemia. PMID:24675553
• Pediatric Blood & Cancer | 2015 | Clinical and genomic heterogeneity of Diamond Blackfan anemia in the Russian Federation. PMID:25946618
• Frontiers in Genetics | 2022 | Deficiency of ribosomal protein S26, which is mutated in a subset of patients with Diamond Blackfan anemia, impairs erythroid differentiation. PMID:36579335

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