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Nature DOI:10.1038/nature06494

Identification of RPS14 as a 5q- syndrome gene by RNA interference screen.

Publication TypeJournal Article
Year of Publication2008
AuthorsEbert, BL, Pretz, J, Bosco, J, Chang, CY, Tamayo, P, Galili, N, Raza, A, Root, DE, Attar, E, Ellis, SR, Golub, TR
Date Published2008 Jan 17
KeywordsAnemia, Diamond-Blackfan, Cell Differentiation, Cells, Cultured, Chromosome Deletion, Chromosomes, Human, Pair 5, Erythroid Cells, Genetic Linkage, Genetic Predisposition to Disease, Hematopoietic Stem Cells, Humans, Phenotype, Ribosomal Proteins, Ribosomes, RNA Interference, RNA Precursors, RNA, Ribosomal, RNA, Ribosomal, 18S, Syndrome

Somatic chromosomal deletions in cancer are thought to indicate the location of tumour suppressor genes, by which a complete loss of gene function occurs through biallelic deletion, point mutation or epigenetic silencing, thus fulfilling Knudson's two-hit hypothesis. In many recurrent deletions, however, such biallelic inactivation has not been found. One prominent example is the 5q- syndrome, a subtype of myelodysplastic syndrome characterized by a defect in erythroid differentiation. Here we describe an RNA-mediated interference (RNAi)-based approach to discovery of the 5q- disease gene. We found that partial loss of function of the ribosomal subunit protein RPS14 phenocopies the disease in normal haematopoietic progenitor cells, and also that forced expression of RPS14 rescues the disease phenotype in patient-derived bone marrow cells. In addition, we identified a block in the processing of pre-ribosomal RNA in RPS14-deficient cells that is functionally equivalent to the defect in Diamond-Blackfan anaemia, linking the molecular pathophysiology of the 5q- syndrome to a congenital syndrome causing bone marrow failure. These results indicate that the 5q- syndrome is caused by a defect in ribosomal protein function and suggest that RNAi screening is an effective strategy for identifying causal haploinsufficiency disease genes.


Alternate JournalNature
PubMed ID18202658
PubMed Central IDPMC3771855
Grant ListR01 HL082945 / HL / NHLBI NIH HHS / United States
R01 HL079583 / HL / NHLBI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
K08 HL078818 / HL / NHLBI NIH HHS / United States