A new murineRpl5(uL18) mutation provides a unique model of variably penetrant Diamond Blackfan Anemia

AbstractRibosome dysfunction is implicated in multiple abnormal developmental and disease states in humans. Heterozygous germline mutations in genes encoding ribosomal proteins (RPs) are found in the majority of individuals with Diamond Blackfan anemia (DBA) while somatic mutations have been implicated in a variety of cancers and other disorders. Ribosomal protein-deficient animal models show variable phenotypes and penetrance, similar to human DBA patients. The spontaneous anemia remission observed in some DBA patients occurs via unknown mechanism(s) and has not been previously described in animal models. Here we characterized a novel ENU mouse mutant (Skax23m1Jus) with growth and skeletal defects, cardiac malformations and increased mortality. Following genetic mapping and whole exome sequencing, we identified an intronicRpl5mutation, which segregated with all affected mice. This mutation was associated with decreased ribosome generation, consistent withRpl5haploinsufficiency.Rpl5Skax23-Jusmutant animals had a profound delay in erythroid maturation and increased mortality at embryonic day E12.5, which improved by E14.5. Surviving mutant animals had a macrocytic anemia at birth as well as evidence of ventricular septal defect (VSD). Surviving adult and aged mice exhibited no hematopoietic defect or VSD. We propose that this novelRpl5Skax23-Jusmutant mouse will be useful to study the factors influencing the variable penetrance and anemia remission that are observed in DBA.