RPS19 – Diamond-Blackfan Anemia

Diamond-Blackfan anemia (DBA; MONDO:0015253) is a congenital pure red-cell aplasia characterized by macrocytic anemia, reticulocytopenia, and a spectrum of congenital anomalies. The ribosomal protein S19 gene (RPS19; HGNC:10402) was the first gene implicated in DBA, and heterozygous variants in RPS19 underlie an autosomal dominant form of the disease (PMID:9988267).

RPS19 pathogenic variants are detected in approximately 25% of DBA cases. In a cohort of 172 unrelated families screened by exon sequencing, RPS19 mutations affecting coding or splice sites were found in 34 families (19.7%) (PMID:10590074). Segregation of heterozygous RPS19 alleles with erythroid aplasia in multiple kindreds—affecting at least 8 additional relatives—supports autosomal dominant inheritance.

Variants cluster in a hotspot between codons 52–62, with examples including c.166C>G (p.Arg56Gly) reported in an infant and his father presenting with early-onset anemia and tachypnea (PMID:27601194). Other classes of pathogenic alleles include nonsense, frameshift (e.g., c.384_385del, p.Asp130fs), and splice-site mutations, reflecting diverse mechanisms of loss of function.

Functional assays demonstrate that RPS19 haploinsufficiency impairs ribosomal biogenesis: patient-derived cells exhibit defective pre-18S rRNA processing and reduced RPS19 protein levels consistent with haploinsufficiency (PMID:15384984). Mutations affecting nucleolar localization signals (e.g., Val15Phe, Gly127Gln) lead to mislocalization and decreased stability of RPS19 (PMID:12586610).

In vivo, rps19 knockdown in zebrafish recapitulates the human phenotype—severe anemia and craniofacial defects—that can be rescued by wild-type rps19 mRNA or leucine supplementation (PMID:18515656). A transgenic mouse model expressing RPS19R62W exhibits dominant-negative effects with growth retardation and anemia, confirming the critical role of RPS19 in erythropoiesis (PMID:20606162).

Collectively, the genetic, segregation, and functional data fulfill ClinGen criteria for a definitive gene–disease relationship. RPS19 testing is recommended for early diagnosis, family counseling, and guiding therapies in suspected DBA. Functional complementation assays aid in the classification of variants of uncertain significance.

Key Take-home: RPS19 haploinsufficiency underlies autosomal dominant DBA, and comprehensive genetic and functional evaluation is essential for accurate diagnosis and management.

References

• Nature Genetics • 1999 • The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. PMID:9988267
• Blood • 1999 • Mutations in ribosomal protein S19 gene and diamond blackfan anemia: wide variations in phenotypic expression. PMID:10590074
• Blood • 2003 • Nucleolar localization of RPS19 protein in normal cells and mislocalization due to mutations in the nucleolar localization signals in 2 Diamond-Blackfan anemia patients: potential insights into pathophysiology. PMID:12586610
• Blood • 2008 • Deficiency of ribosomal protein S19 during early embryogenesis leads to reduction of erythrocytes in a zebrafish model of Diamond-Blackfan anemia. PMID:18653748
• Blood • 2010 • A transgenic mouse model demonstrates a dominant negative effect of a point mutation in the RPS19 gene associated with Diamond-Blackfan anemia. PMID:20606162
• Pediatrics International • 2016 • Critical Diamond-Blackfan anemia due to ribosomal protein S19 missense mutation. PMID:27601194

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