ZFIN ID: ZDB-PUB-140516-3
Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multi-case Diamond-Blackfan anemia families
Mirabello, L., Macari, E.R., Jessop, L., Ellis, S.R., Myers, T., Giri, N., Taylor, A.M., McGrath, K.E., Humphries, J.M., Ballew, B.J., Yeager, M., Boland, J.F., He, J., Hicks, B.D., Burdett, L., Alter, B.P., Zon, L., Savage, S.A.
Diamond-Blackfan anemia (DBA) is a cancer-prone inherited bone marrow failure syndrome. Approximately half of DBA patients have a germline mutation in a ribosomal protein gene. We used whole-exome sequencing to identify disease-causing genes in two large DBA families. After filtering, one nonsynonymous mutation (p.I31F) in the ribosomal protein S29 (RPS29) gene was present in all 5 DBA affected individuals and the obligate carrier, and absent from the unaffected non-carrier parent in one DBA family. A second DBA family was found to have a different nonsynonymous mutation (p.I50T) in RPS29. Both mutations are amino acid substitutions in exon 2 predicted to be deleterious, and resulted in haploinsufficiency of RPS29 expression compared with wildtype RPS29 expression from an unaffected control. The DBA proband with the p.I31F RPS29 mutation had a pre-rRNA processing defect compared to the healthy control. We demonstrated that both RPS29 mutations failed to rescue the defective erythropoiesis in the rps29(-/-) mutant zebrafish DBA model. RPS29 is a component of the small 40S ribosomal subunit and essential for ribosomal RNA processing and ribosome biogenesis. We uncovered a novel DBA causative gene, RPS29, and showed that germline mutations in RPS29 can cause a defective erythropoiesis phenotype using a zebrafish model.