Creation of a Ribosomal Protein Sa/LAMR1 Heterozygous Mouse.

Diamond Blackfan anemia (DBA) is a severe hypoplastic anemia that generally presents early in infancy. Approximately 25% of DBA cases have been linked to mutations in the gene encoding ribosomal protein S19. The remaining cases are of unknown etiology. Our studies in yeast have identified a specific role for Rps19 in the maturation of 40S ribosomal subunits. While only one other small subunit ribosomal protein, Rps18, has a function virtually identical to Rps19 in subunit maturation, several others have functions closely related to Rps19. If the involvement of Rps19 in DBA is linked to its role in the synthesis of 40S ribosomal subunits, we would expect that one or more of these other ribosomal proteins may be responsible for DBA in patients with normal RPS19. To address a potential role for ribosomal proteins other than Rps19 in DBA we have created a transgenic mouse heterozygous at the LAMR1 locus. LAMR1 encodes ribosomal protein Sa, the mammalian homolog of the yeast ribosomal protein S0. Rps0, like Rps19, is required for the maturation of the 3′ end of 18S rRNA. We are currently in the fourth generation of out-crossing the original 129SvEv/C57BL6J chimeras to a C57BL6 background. The frequency of heterozygous pups is about that expected by Mendelian segregation suggesting that haploinsufficiency for ribosomal protein Sa does not lead to significant embryonic lethality. The heterozygous mice do, however, exhibit a higher frequency of craniofacial abnormalities and premature deaths relative to their wild-type littermates. The overall fitness of the heterozygous mice appears to be decreasing with each generation of outcrossing to the C57/BL6 background. Efforts are underway to understand the nature of the premature deaths and to obtain detailed hematological profiles on the LAMR1 heterozygous mice.