Ribosomopathies: human disorders of ribosome dysfunction - PubMed (original) (raw)

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Ribosomopathies: human disorders of ribosome dysfunction

Anupama Narla et al. Blood. 2010.

Abstract

Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, Schwachman-Diamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q- syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases.

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Figures

Figure 1

Figure 1

Simplified schematic of eukaryotic ribosome biogenesis. Adapted from Liu and Ellis with permission.

Figure 2

Figure 2

Selected physical abnormalities seen in ribosomopathies. (A) Left panel: Patient with DBA, illustrating the characteristic craniofacial abnormalities (courtesy of J. Lipton). Note the absent lower eyelashes, deformed external ears, and micrognathia. Second panel: An example of the triphalangeal thumb seen in DBA patients (courtesy of E. Atsidaftos and E. Muir). First panel: Reprinted from Lipton and Ellis with permission. (B) These panels illustrate the diagnostic triad of DKC, including dystrophic fingernails, lacy/reticular pigmentation on neck and trunk, and oral leukoplakia (courtesy of B. Alter). Reprinted from Savage and Alter with permission. (C) The craniofacial abnormalities of a patient with TCS are illustrated (courtesy of M. R. Passos Bueno). Note the down slanting palpebral fissures, malar and maxillary hypoplasia, and malformation of the ears. Reprinted from Passos-Bueno et al with permission.

Figure 3

Figure 3

Potential mechanisms for the cellular consequences of ribosomal haploinsufficiency. (A) Top panel: Normal cell in unstressed conditions, with unperturbed ribosome biogenesis and steady levels of p53. Bottom panel: Ribosomal haploinsufficiency leads to up-regulation of rpL11, which binds to MDM2 causing p53 activation, which results in apoptosis and cell-cycle arrest. (B) Top panel: Normal hemoglobin synthesis, with the coordinated production of heme and globin. Bottom panel: Relative excess of free heme leads to oxidative stress and hemolysis through a variety of mechanisms.

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