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

By Benjamin L. Ebert, J. Pretz, Jocelyn Bosco, Cindy Y. Chang, Pablo Tamayo, N. Galili, A. Raza, D. Root, E. Attar, S. Ellis and 1 more. Nature, 2008

947 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/922d0f1f7bbfe3492007ec45cad2dce67d249d47

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Citations in the corpus

Ribosomopathies: human disorders of ribosome dysfunction. (2010, background): “RPS14 was identified as a 5q- syndrome gene in an RNA interference screen of each gene within the 5qsyndrome common deleted region (CDR).[3, 31] In patients with the 5q- syndrome, one allele of RPS14 is deleted [3] and haploinsufficient expression of RPS14 has been confirmed in patient samples.”
Ribosomal proteins: functions beyond the ribosome. (2015, background): “…al. (2008), Farrar et al. (2008), Doherty et al. (2010), Landowski et al. (2013), Gripp et al. (2014) and Mirabello et al. (2014) 5q-syndrome S14 Ebert et al. (2008) and Barlow et al. (2010) Isolated congenital asplenia (ICA) SA Bolze et al. (2013) Autism L10 Klauck et al. (2006) Hereditary…”
Mutations of polycomb‐associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia (2009, background): “Except in few specific cases (Ebert et al, 2008), the pathophysiology of MDS remains unclear, but a multistep sequence has been proposed as a model of pathogenesis.”
Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts (2011, neutral): “T663A K666N (5); K666Q (1); K666R (4); K666T (2)”
RECURRENT MUTATIONS IN THE U2AF1 SPLICING FACTOR IN MYELODYSPLASTIC SYNDROMES (2011, background): “POU4F1 is associated with t(8;21) acute myeloid leukemia and contributes directly to its unique transcriptional signature.”
How Common are Extra-ribosomal Functions of Ribosomal Proteins? (2009, background): “This 5q syndrome is due to the loss of one copy of the gene for S14 (Ebert et al., 2008).”