Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families

Mirabello, Lisa; Macari, Elizabeth R.; Jessop, Lea; Ellis, Steven R.; Myers, Timothy A.; Giri, Neelam; Taylor, Alison M.; McGrath, Katherine; Humphries, Jessica M.; Ballew, Bari J.; Yeager, Meredith; Boland, Joseph F.; He, Ji; Hicks, Belynda; Burdett, Laurie; Alter, Blanche P.; Zon, Leonard I.; Savage, Sharon A.

doi:10.1182/blood-2013-11-540278

Cited by 82 publications

(51 citation statements)

References 42 publications

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“…Mutations in ribosomal protein genes, such as rps29 , cause DBA-like anemia in zebrafish (24). RPS29 is also mutated in a subset of DBA patients (25). Rps29 − / − zebrafish are anemic, as revealed by lack of hemoglobin staining in the yolk sac; treatment with SMER28 for 40 hours postfertilization (hpf) increased hemoglobin staining (Fig.…”

Section: Resultsmentioning

confidence: 99%

Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors

Doulatov

Macari

et al. 2017

Sci. Transl. Med.

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Diamond-Blackfan anemia (DBA) is a congenital disorder characterized by the failure of erythroid progenitor differentiation, severely curtailing red blood cell production. Because many DBA patients fail to respond to corticosteroid therapy, there is considerable need for therapeutics for this disorder. Identifying therapeutics for DBA requires circumventing the paucity of primary patient blood stem and progenitor cells. To this end, we adopted a reprogramming strategy to generate expandable hematopoietic progenitor cells from induced pluripotent stem cells (iPSCs) from DBA patients. Reprogrammed DBA progenitors recapitulate defects in erythroid differentiation, which were rescued by gene complementation. Unbiased chemical screens identified SMER28, a small-molecule inducer of autophagy, which enhanced erythropoiesis in a range of in vitro and in vivo models of DBA. SMER28 acted through autophagy factor ATG5 to stimulate erythropoiesis and up-regulate expression of globin genes. These findings present an unbiased drug screen for hematological disease using iPSCs and identify autophagy as a therapeutic pathway in DBA.

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Section: Resultsmentioning

confidence: 99%

Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors

Doulatov

Macari

et al. 2017

Sci. Transl. Med.

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“…Additional RPs besides the ones described above show differential expression in cancer, often because of copy number changes (86, 87). Thus further investigations are needed to elucidate the role of the deletions and amplifications of ribosomal protein genes in cancer.…”

Section: Defects In Ribosome Biogenesis Ribosomal Proteins and Ribosmentioning

confidence: 99%

How Ribosomes Translate Cancer

et al. 2017

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A wealth of novel findings, including congenital ribosomal mutations in ribosomopathies and somatic ribosomal mutations in various cancers, have significantly increased our understanding of the relevance of ribosomes in oncogenesis. Here we explore the growing list of mechanisms by which the ribosome is involved in carcinogenesis – from the hijacking of ribosomes by oncogenic factors and dysregulated translational control, to the effects of mutations in ribosomal components on cellular metabolism. Of clinical importance, the recent success of RNA polymerase inhibitors highlights the dependence on “onco-ribosomes” as an Achilles’ heel of cancer cells and a promising target for further therapeutic intervention.

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“…In addition, the organ development in zebrafish is highly similar to that in humans (7,8) and the zebrafish genome contains more than 70% of human genes (9). Indeed, zebrafish has already become a common laboratory animal for in vivo validation of candidate disease genes identified from genome-wide association studies (GWAS) as well as WES (10–14). Furthermore, zebrafish embryos containing genetic defects of human diseases enable high throughput drug screening and toxicity tests in vivo (15) and facilitate the investigation of disease mechanisms through various molecular and genomics techniques suitable for the organism (7).…”

Section: Introductionmentioning

confidence: 99%

Function-driven discovery of disease genes in zebrafish using an integrated genomics big data resource

Shim

Kim

et al. 2016

Nucleic Acids Res

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Whole exome sequencing (WES) accelerates disease gene discovery using rare genetic variants, but further statistical and functional evidence is required to avoid false-discovery. To complement variant-driven disease gene discovery, here we present function-driven disease gene discovery in zebrafish (Danio rerio), a promising human disease model owing to its high anatomical and genomic similarity to humans. To facilitate zebrafish-based function-driven disease gene discovery, we developed a genome-scale co-functional network of zebrafish genes, DanioNet (www.inetbio.org/danionet), which was constructed by Bayesian integration of genomics big data. Rigorous statistical assessment confirmed the high prediction capacity of DanioNet for a wide variety of human diseases. To demonstrate the feasibility of the function-driven disease gene discovery using DanioNet, we predicted genes for ciliopathies and performed experimental validation for eight candidate genes. We also validated the existence of heterozygous rare variants in the candidate genes of individuals with ciliopathies yet not in controls derived from the UK10K consortium, suggesting that these variants are potentially involved in enhancing the risk of ciliopathies. These results showed that an integrated genomics big data for a model animal of diseases can expand our opportunity for harnessing WES data in disease gene discovery.

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Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families

Cited by 82 publications

References 42 publications

Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors

Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors

How Ribosomes Translate Cancer

Function-driven discovery of disease genes in zebrafish using an integrated genomics big data resource

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