Dissecting the transcriptional phenotype of ribosomal protein deficiency: implications for Diamond-Blackfan Anemia

Aspesi, Anna; Pavesi, Elisa; Robotti, Elisa; Crescitelli, Rossella; Boria, Ilenia; Avondo, Federica; Moniz, Hélène; Costa, Lydie Da; Mohandas, Narla; Roncaglia, Paola; Ramenghi, Ugo; Ronchi, Antonella; Gustincich, Stefano; Merlin, Simone; Marengo, Emílio; Ellis, Steven R.; Follenzi, Antonia; Santoro, Claudio; Dianzani, Irma

doi:10.1016/j.gene.2014.04.077

Cited by 31 publications

(34 citation statements)

References 42 publications

(49 reference statements)

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“…Essential information regarding the cellular changes associated with ribosomal mutations remains to be discovered. While mRNA expression studies may provide certain clues, 42,43,44,45 given that protein translation is the central function of ribosomes, it may be essential to complement these studies by a detailed analysis of the effects on protein production. This necessity is illustrated by the recent finding that in a substantial fraction of DBA cases, one consequence of the ribosomal protein mutations is failure of translation of the transcription factor GATA-1, an essential factor for development of erythropoiesis beyond the CFU-E stage.…”

Section: Future Perspectives and Conclusionmentioning

confidence: 99%

Ribosomopathies and the paradox of cellular hypo- to hyperproliferation

Keersmaecker

Sulima

Dinman

2015

Blood

100

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Ribosomopathies are largely congenital diseases linked to defects in ribosomal proteins or biogenesis factors. Some of these disorders are characterized by hypoproliferative phenotypes such as bone marrow failure and anemia early in life, followed by elevated cancer risks later in life. This transition from hypo- to hyperproliferation presents an intriguing paradox in the field of hematology known as ‘Dameshek’s riddle.’ Recent cancer sequencing studies also revealed somatically acquired mutations and deletions in ribosomal proteins in T-cell acute lymphoblastic leukemia (T-ALL) and solid tumors, further extending the list of ribosomopathies and strengthening the association between ribosomal defects and oncogenesis. In this perspective, we summarize and comment on recent findings in the field of ribosomopathies. We explain how ribosomopathies may provide clues to help explain Dameshek’s paradox and highlight some of the open questions and challenges in the field.

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Section: Future Perspectives and Conclusionmentioning

confidence: 99%

Ribosomopathies and the paradox of cellular hypo- to hyperproliferation

Keersmaecker

Sulima

Dinman

2015

Blood

100

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“…We modeled our hypothesis on reports from a clinically distinct ribosomopathy, Diamond-Blackfan anemia (DBA), in which mutations in ribosomal proteins can result in cell cycle arrest or induction of apoptosis (Aspesi et al 2014). For example, studies using patient cells harboring mutations in the most common DBA gene, RPS19, can give rise to altered proliferation (Kuramitsu et al 2008) and/or cell death (Gazda et al 2006;Choesmel et al 2007).…”

Section: Rpl10 Morphants Display Augmented Apoptosis In the Brainmentioning

confidence: 99%

A Novel Ribosomopathy Caused by Dysfunction of RPL10 Disrupts Neurodevelopment and Causes X-Linked Microcephaly in Humans

et al. 2014

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Neurodevelopmental defects in humans represent a clinically heterogeneous group of disorders. Here, we report the genetic and functional dissection of a multigenerational pedigree with an X-linked syndromic disorder hallmarked by microcephaly, growth retardation, and seizures. Using an X-linked intellectual disability (XLID) next-generation sequencing diagnostic panel, we identified a novel missense mutation in the gene encoding 60S ribosomal protein L10 (RPL10), a locus associated previously with autism spectrum disorders (ASD); the p.K78E change segregated with disease under an X-linked recessive paradigm while, consistent with causality, carrier females exhibited skewed X inactivation. To examine the functional consequences of the p.K78E change, we modeled RPL10 dysfunction in zebrafish. We show that endogenous rpl10 expression is augmented in anterior structures, and that suppression decreases head size in developing morphant embryos, concomitant with reduced bulk translation and increased apoptosis in the brain. Subsequently, using in vivo complementation, we demonstrate that p.K78E is a loss-of-function variant. Together, our findings suggest that a mutation within the conserved N-terminal end of RPL10, a protein in close proximity to the peptidyl transferase active site of the 60S ribosomal subunit, causes severe defects in brain formation and function. N EURODEVELOPMENTAL defects in humans represent a diagnostic challenge. Displaying marked phenotypic overlap, examples include autism spectrum disorders (ASD), intellectual disability (ID), microcephaly, and seizures; in some instances, common genetic defects can underscore each of these clinical entities. For example, mutations in the voltage-gated sodium channel Na v 1.2 encoded by SCN2A are associated with the manifestation of early infantile epilepsy (Sugawara et al. 2001). However, recent exome sequencing studies have also identified SCN2A mutations as rare contributors to disease in autism cohorts, thereby expanding the phenotypic spectrum underscored by Na v 1.2 channel dysfunction (Sanders et al. 2012). A gender bias of 1.3-1.4 males to 1 female with a neurodevelopmental disorder has complicated further our mechanistic understanding of such defects (Leonard and Wen 2002;Ellison et al. 2013). One obvious explanation for an unbalanced representation of the sexes among individuals with a structural or functional brain defect is an abundance of developmentally important genes on the X chromosome. To date, .100 genes have been associated with ASD, ID, microcephaly, or seizures primarily in hemizygous males and, to some extent, their carrier mothers (De Brouwer et al. 2007;Tarpey et al. 2009;Lubs et al. 2012).Here, we report the genetic dissection of a novel form of X-linked human genetic disease characterized by microcephaly, seizures, growth retardation, and hypotonia. Combined genetic, functional, and biochemical assays suggest that a missense mutation in RPL10, a component of the 60S large ribosomal subunit, can cause syndromic central nervo...

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“…It lies in close proximity to RPS13, RPS16, and RPS19, which are involved in elongation initiation factor 2 (eIF-2) binding (29). RPS17 along with RPS19 and RPS24 has been linked to diseases in humans, including Diamond-Blackfan anemia (30,31), an erythroid aplasia resulting in a deficiency of red blood cell precursors in the bone marrow. In Escherichia coli, RPS17 is one of the six proteins which bind independently to 16S rRNA (30).…”

mentioning

confidence: 99%

The Lysine Residues within the Human Ribosomal Protein S17 Sequence Naturally Inserted into the Viral Nonstructural Protein of a Unique Strain of Hepatitis E Virus Are Important for Enhanced Virus Replication

Kenney

Meng

2015

J Virol

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Hepatitis E virus (HEV) is an important but extremely understudied human pathogen. Due largely to the lack of an efficient cell culture system for HEV, the molecular mechanisms of HEV replication and pathogenesis are poorly understood. Recently, a unique genotype 3 strain of HEV recovered from a chronically infected patient was adapted for growth in HepG2C3A human hepatoma cells. The adaptation of the Kernow C-1 P6 HEV to propagate in HepG2C3A cells selected for a rare virus recombinant that contains an insertion of a 171-nucleotide sequence encoding amino acids 21 to 76 of the human ribosomal protein S17 (RPS17) within the hypervariable region (HVR) of the HEV ORF1 protein. When the RPS17 insertion was placed into a strain of genotype 1 HEV which infects only humans, it expanded the host range of the virus, allowing it to infect cell lines from multiple animal species, including cow, dog, cat, chicken, and hamster. In this study, we utilized forward and reverse genetics to attempt to define which aspects of the RPS17 insertion allow for the ability of the Kernow C-1 P6 HEV to adapt in cell culture and allow for expanded host tropism. We demonstrate that the RPS17 sequence insertion in HEV bestows novel nuclear/nucleolar trafficking capabilities to the ORF1 protein of Kernow P6 HEV and that lysine residues within the RPS17 insertion, but not nuclear localization of the ORF1 protein, correlate with the enhanced replication of the HEV Kernow C-1 P6 strain. The results from this study have important implications for understanding the mechanism of cross-species infection and replication of HEV. IMPORTANCEHEV is an important pathogen worldwide. The virus causes high mortality (up to 30%) in pregnant women and has been recognized to cause chronic hepatitis in immunocompromised populations. The life cycle of HEV has been understudied due to a lack of sufficient cell culture systems in which to propagate the virus. Recently, insertions and rearrangements of the hypervariable region (HVR) within the HEV genome, allowing for cell culture adaptation and expansion of the host range, have been reported. We utilized these cell culture-adapted HEV strains to assess how the HVR may be involved in virus replication and host range. We provide evidence that insertion of the RPS17 sequence in HEV likely confers nuclear trafficking capabilities to the nonstructural protein of the virus and that lysine residues within the RPS17 insertion are important for enhanced replication of the virus. These data will help to elucidate the mechanism of cross-species infection of HEV in the future. Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis in many parts of the world (1, 2). Major outbreaks and epidemics are most common in developing countries, where a lack of proper sanitation conditions leads to waterborne spread of the disease. In industrialized countries, HEV infection is typically sporadic and endemic. Recently, chronic HEV infection has become an important clinical problem in immunosuppressed individual...

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Dissecting the transcriptional phenotype of ribosomal protein deficiency: implications for Diamond-Blackfan Anemia

Cited by 31 publications

References 42 publications

Ribosomopathies and the paradox of cellular hypo- to hyperproliferation

Ribosomopathies and the paradox of cellular hypo- to hyperproliferation

A Novel Ribosomopathy Caused by Dysfunction of RPL10 Disrupts Neurodevelopment and Causes X-Linked Microcephaly in Humans

The Lysine Residues within the Human Ribosomal Protein S17 Sequence Naturally Inserted into the Viral Nonstructural Protein of a Unique Strain of Hepatitis E Virus Are Important for Enhanced Virus Replication

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