RPL5 – Diamond-Blackfan anemia

Ribosomal protein L5 (RPL5) is a core component of the 60S ribosomal subunit whose haploinsufficiency leads to Diamond-Blackfan anemia (DBA), a congenital erythroid aplasia. DBA typically manifests with normochromic macrocytic anemia, reticulocytopenia, and physical malformations such as craniofacial anomalies, thumb defects, and growth retardation. Heterozygous RPL5 mutations account for approximately 7–10% of DBA cases and are strongly associated with multiple somatic anomalies, notably cleft palate and thumb abnormalities (PMID:19061985; PMID:19191325).

Genetic evidence supports an autosomal dominant inheritance for RPL5-related DBA, with de novo and familial cases described. To date, over 50 unrelated patients harbor truncating or splice-site mutations in RPL5, including frameshifts (e.g., c.392dup (p.Asn131LysfsTer6)) and deep intronic variants disrupting normal splicing (PMID:38004002; PMID:30503522). Segregation analysis in at least six multiplex families demonstrates co-segregation of RPL5 variants with DBA phenotype and absence of the variant in unaffected relatives (PMID:19191325).

The variant spectrum in RPL5 is dominated by loss-of-function alleles: nonsense, frameshift, splice-site, and exon deletions. No recurrent founder variants have been reported, underscoring diverse mutational mechanisms. Carrier frequency in population databases is negligible, consistent with disease penetrance and allele rarity.

Functional studies corroborate the pathogenic mechanism of RPL5 haploinsufficiency. Murine ENU mutants with an intronic Rpl5 lesion exhibit macrocytic anemia and cardiac malformations mirroring human DBA (PMID:34464976). Murine embryonic stem cells haploinsufficient for Rpl5 demonstrate delayed G2/M progression and impaired erythroid colony formation that is not solely p53-dependent (PMID:24558476). Polysome profiling in patient B-cells reveals reduced 60S and 80S ribosomal subunits, confirming ribosome biogenesis defects in RPL5-deficient cells (PMID:33122585).

No studies have refuted the RPL5–DBA association. Integration of genetic, segregation, and functional data meets ClinGen criteria for a Definitive gene–disease relationship. Further longitudinal studies may elucidate modifiers of penetrance and variability in the non-erythroid phenotype.

Key Take-home: Heterozygous loss-of-function RPL5 variants cause autosomal dominant DBA via haploinsufficiency, with robust genetic and experimental evidence supporting clinical diagnostic testing and targeted genetic counseling.

References

• American journal of human genetics • 2008 • Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. PMID:19061985
• Human mutation • 2009 • Identification of mutations in the ribosomal protein L5 (RPL5) and ribosomal protein L11 (RPL11) genes in Czech patients with Diamond-Blackfan anemia. PMID:19191325
• American journal of human genetics • 2018 • The Genetic Landscape of Diamond-Blackfan Anemia. PMID:30503522
• PLoS One • 2014 • p53-Independent cell cycle and erythroid differentiation defects in murine embryonic stem cells haploinsufficient for Diamond Blackfan anemia-proteins: RPS19 versus RPL5. PMID:24558476
• Blood advances • 2021 • A new murine Rpl5 (uL18) mutation provides a unique model of variably penetrant Diamond-Blackfan anemia. PMID:34464976
• Medicina (Kaunas, Lithuania) • 2023 • A De Novo Frameshift Mutation in RPL5 with Classical Phenotype Abnormalities and Worsening Anemia Diagnosed in a Young Adult-A Case Report and Review of the Literature. PMID:38004002

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