RPS26 – Diamond-Blackfan anemia 10

Diamond-Blackfan anemia type 10 (DBA10; MONDO:0013217) is a congenital pure red cell aplasia characterized by normochromic macrocytic anemia, reticulocytopenia, and near‐absent erythroid progenitors in the bone marrow. RPS26 (HGNC:10414) encodes a 40S ribosomal subunit protein essential for rRNA maturation and ribosome assembly. DBA10 follows autosomal dominant inheritance with heterozygous pathogenic variants in RPS26 disrupting ribosome biogenesis. Clinically, patients present in infancy with severe anemia and low reticulocyte counts ([PMID:31277601]). Genetic testing identifies causative RPS26 variants, guiding diagnosis and management. Here we summarize the genetic and functional evidence supporting the RPS26–DBA10 association.

Genetic evidence includes over 30 distinct heterozygous RPS26 variants reported across unrelated probands ([PMID:31277601]), comprising missense, nonsense, frameshift, and splice-site alleles. A recurrent truncating variant, c.259C>T (p.Arg87Ter), exemplifies a loss-of-function mechanism and has been observed in multiple families ([PMID:24942156]). A novel frameshift insertion, c.96dupG (p.Ser33ValfsTer31), was identified in a three-month-old Chinese male with neonatal onset anemia, expanding the mutation spectrum of DBA10 ([PMID:31277601]). These variants cluster throughout the coding region, indicating no clear mutational hotspot but consistent functional consequence. Allele frequency data support rarity in population databases, reinforcing pathogenicity. Together, these findings fulfill strong genetic criteria under ClinGen guidelines.

Segregation analysis is limited by predominantly de novo presentations, though familial cases have been described. In a cohort of six unrelated probands with combined Treacher-Collins/macrofacial features and anemia, two families harbored heterozygous RPS26 variants—one splice-site (c.4-2A>T) and one truncating (c.259C>T (p.Arg87Ter))—demonstrating recurrence and autosomal dominant inheritance ([PMID:24942156]). Penetrance appears high, with affected individuals displaying classic DBA features in each family. No unaffected carriers have been reported, consistent with haploinsufficiency. Large multi-generation pedigrees are lacking, but available segregation data substantiate variant pathogenicity. No conflicting segregation evidence has been documented.

Functional studies provide moderate experimental support for RPS26 haploinsufficiency in DBA pathogenesis. RPS26 knockdown in human umbilical cord blood erythroid progenitors (HUDEP-1) impairs erythroid differentiation, upregulates pro-apoptotic genes, disrupts rRNA balance, and decreases cell viability, recapitulating cellular hallmarks of DBA ([PMID:36579335]). Site-directed mutagenesis of the eukaryote-specific YxxPKxYxK motif in the C-terminal tail alters translation initiation and polysome assembly in HEK293T cells, implicating disrupted mRNA binding in the mechanism ([PMID:35817369]). These concordant models support a loss-of-function mechanism consistent with human phenotypes. Rescue experiments in these systems remain to be reported. Overall, experimental data meet moderate ClinGen thresholds.

Mechanistically, heterozygous RPS26 variants lead to ribosome biogenesis defects, activating p53-mediated apoptosis in erythroid progenitors and resulting in anemia. The absence of dominant-negative or gain-of-function effects aligns with a haploinsufficiency model. Impaired ribosomal assembly reduces global protein synthesis, with disproportionate impact on rapidly dividing erythroid precursors. No alternative molecular mechanisms have been substantiated. Combined genetic and functional data robustly link RPS26 deficiency to DBA10.

Genetic testing for RPS26 should be included in diagnostic panels for congenital anemia given the strong gene-disease association and autosomal dominant inheritance. Identification of heterozygous LoF RPS26 variants informs clinical management, genetic counseling, and family planning. Future research should explore genotype–phenotype correlations, modifier genes, and therapeutic rescue strategies. Key Take-home: RPS26 haploinsufficiency is a well‐supported, clinically actionable cause of autosomal dominant Diamond-Blackfan anemia type 10.

References

• BMC medical genetics • 2019 • Identification of a novel RPS26 nonsense mutation in a Chinese Diamond-Blackfan Anemia patient. PMID:31277601
• American journal of medical genetics. Part A • 2014 • Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28. PMID:24942156
• 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
• Biochimica et biophysica acta. Gene regulatory mechanisms • 2022 • The functional role of the eukaryote-specific motif YxxPKxYxK of the human ribosomal protein eS26 in translation. PMID:35817369

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