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Irma Dianzani - One of the best experts on this subject based on the ideXlab platform.

  • High frequency of ribosomal protein gene deletions in Italian Diamond-Blackfan Anemia patients detected by multiplex ligation-dependent probe amplification assay
    Haematologica, 2012
    Co-Authors: Paola Quarello, Irma Dianzani, Emanuela Garelli, Adriana Carando, Alfredo Brusco, Luciana Vinti, Cecilia Mancini, Patrizia Pappi, Johanna Svahn, Ugo Ramenghi
    Abstract:

    Diamond-Blackfan Anemia is an autosomal dominant disease due to mutations in nine ribosomal protein encoding genes. Because most mutations are loss of function and detected by direct sequencing of coding exons, we reasoned that part of the approximately 50% mutation negative patients may have carried a copy number variant of ribosomal protein genes. As a proof of concept, we designed a multiplex ligation-dependent probe amplification assay targeted to screen the six genes that are most frequently mutated in Diamond-Blackfan Anemia patients: RPS17, RPS19, RPS26, RPL5, RPL11, and RPL35A. Using this assay we showed that deletions represent approximately 20% of all mutations. The combination of sequencing and multiplex ligation-dependent probe amplification analysis of these six genes allows the genetic characterization of approximately 65% of patients, showing that Diamond-Blackfan Anemia is indisputably a ribosomopathy.

  • Clinical utility gene card for: Diamond Blackfan Anemia
    European Journal of Human Genetics, 2011
    Co-Authors: Adrianna Vlachos, Irma Dianzani, Niklas Dahl, Jeffrey M. Lipton
    Abstract:

    European Journal of Human Genetics advance online publication, 19 January 2011; doi:10.1038/ejhg.2010.2471. DISEASE CHARACTERISTICS1.1 Name of the disease (synonyms)Diamond Blackfan Anemia, DBA1, 3–10 (DBA2 not confirmed), AaseSmith syndrome, congenital hypoplastic Anemia, Blackfan DiamondAnemia and inherited erythroblastopenia.1.2 OMIM# of the disease105650, 610629, 612527, 612528, 612561,612562, 612563, 613308 and613309.1.3 Name of the analysed genes or DNA/chromosome segmentsRPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10 andRPS26.1.4 OMIM# of the gene(s)603474, 602412, 180472, 180468, 603634, 604175, 603658, 603632 and603701.1.5 Mutational spectrumIn patients for whom there is a known mutation (50–60%), DiamondBlackfan Anemia results from a ribosomal protein haploinsufficiency.

  • Clinical utility gene card for: Diamond Blackfan Anemia
    European Journal of Human Genetics, 2011
    Co-Authors: Adrianna Vlachos, Irma Dianzani, Niklas Dahl, Jeffrey M. Lipton
    Abstract:

    European Journal of Human Genetics advance online publication, 19 January 2011; doi:10.1038/ejhg.2010.2471. DISEASE CHARACTERISTICS1.1 Name of the disease (synonyms)Diamond Blackfan Anemia, DBA1, 3–10 (DBA2 not confirmed), AaseSmith syndrome, congenital hypoplastic Anemia, Blackfan DiamondAnemia and inherited erythroblastopenia.1.2 OMIM# of the disease105650, 610629, 612527, 612528, 612561,612562, 612563, 613308 and613309.1.3 Name of the analysed genes or DNA/chromosome segmentsRPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10 andRPS26.1.4 OMIM# of the gene(s)603474, 602412, 180472, 180468, 603634, 604175, 603658, 603632 and603701.1.5 Mutational spectrumIn patients for whom there is a known mutation (50–60%), DiamondBlackfan Anemia results from a ribosomal protein haploinsufficiency.

  • a new database for ribosomal protein genes which are mutated in diamond blackfan Anemia
    Human Mutation, 2008
    Co-Authors: Ilenia Boria, Irma Dianzani, Paola Quarello, Emanuela Garelli, Adriana Carando, Anna Aspesi, Maria Francesca Campagnoli, Federica Avondo, Ugo Ramenghi
    Abstract:

    Mutations in ribosomal proteins RPS19, RPS24 and RPS17 have been reported in Diamond-Blackfan Anemia (DBA), an autosomal dominant disease characterised by pure red cell aplasia. DBA is the prototype of ribosomapathies: a protein synthesis defect in a tissue with a high cellular turnover is considered the cause of the erythroid progenitor failure. We have created the Diamond-Blackfan Anemia mutation database to curate and record DBA gene mutations, together with their functional consequences and clinical phenotypes. This locus-specific resource is open to future submissions and is available online (http://www.dbagenes.unito.it). It is founded on the Leiden Open (source) Variation Database (LOVD) system and includes data from sequence and structure analysis tools, genomic database resources and published reports. It lists all identified variants and background genomic information. Phenotypic data are accessed by selecting a particular mutation. The database includes 219 unique variants of which 86 are disease-causing mutations. The database will be supplemented with other DBA genes as soon as they are reported and their mutations are identified and it should be of assistance to clinicians and investigators involved in DBA research and care. © 2008 Wiley-Liss, Inc.

  • Multiplex ligation-dependent probe amplification enhances molecular diagnosis of Diamond-Blackfan Anemia due to RPS19 deficiency.
    Haematologica, 2008
    Co-Authors: Paola Quarello, Irma Dianzani, Emanuela Garelli, Adriana Carando, Alfredo Brusco, Patrizia Pappi, Marco Barberis, Valentina Coletti, Maria Francesca Campagnoli, Ugo Ramenghi
    Abstract:

    Diamond-Blackfan Anemia (DBA,#MIM105650) is a rare congenital pure red cell aplasia characterized by nor-mochromic macrocytic Anemia, reticulocytopenia, and normocellular bone marrow with a selective deficiency of erythroid precursors. Defects in the RPS19 gene on chromosome 19q13.2 are the main

Jeffrey M. Lipton - One of the best experts on this subject based on the ideXlab platform.

  • Diamond-Blackfan Anemia
    Pediatric Oncology, 2018
    Co-Authors: Shilpa M. Hattangadi, Jeffrey M. Lipton
    Abstract:

    Diamond-Blackfan Anemia (DBA) is a rare inherited bone marrow failure syndrome (IBMFS) that presents in early infancy and is characterized by severe Anemia with mild macrocytosis, reticulocytopenia, and a normocellular bone marrow with a paucity of erythroid precursors. Clinically DBA is typified by failure of red cell terminal differentiation, an array of physical anomalies, and a predisposition to malignancy. Notably the study of DBA has defined a class of IBMFS referred to as “ribosomopathies” as the pathogenesis of DBA involves predominantly (in about 65–70% of patients) autosomal dominant mutations resulting in haploinsufficiency of ribosomal proteins (RP) encoded by 16 verified genes. X-linked mutations in two non-ribosomal genes, GATA1, encoding an erythroid transcription factor, and TSR2, encoding the putative RPS26 chaperone, are responsible for very rare instances of DBA. Tremendous progress using zebrafish and mouse models of DBA has advanced our understanding of the role of nucleolar stress (p53-dependent) and p53-independent mechanisms in the development of the DBA phenotype, providing strategies for therapeutic intervention. DBA is also confirmed to be a cancer predisposition syndrome. Our increasing understanding of the pathophysiology of DBA is leading to new therapeutic approaches such as ongoing open trials involving the modulation of mTOR and the TGFβ/activin pathways, with agents leucine and Sotatercept, respectively. In addition, trials with HDAC inhibitors, prolyl hydroxylase inhibitors, or PPAR-α agonists that are ongoing in other Anemias may also provide useful insights for directing future therapies for patients with DBA.

  • Endocrine Dysfunction in Diamond-Blackfan Anemia (DBA): A Report from the DBA Registry (DBAR).
    Pediatric blood & cancer, 2015
    Co-Authors: Amit Lahoti, Jeffrey M. Lipton, Evangelia Atsidaftos, Yael T. Harris, Phyllis W. Speiser, Adrianna Vlachos
    Abstract:

    Objective Diamond Blackfan Anemia (DBA) is a rare inherited bone marrow failure syndrome. The mainstays of treatment involve chronic red cell transfusions, long-term glucocorticoid therapy, and stem cell transplantation. Systematic data concerning endocrine function in DBA are limited. We studied patients in the DBA Registry (DBAR) of North America to assess the prevalence of various endocrinopathies.

  • Diamond Blackfan Anemia: a model for the translational approach to understanding human disease
    Expert review of hematology, 2014
    Co-Authors: Adrianna Vlachos, Lionel Blanc, Jeffrey M. Lipton
    Abstract:

    Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome. As with the other rare inherited bone marrow failure syndromes, the study of these disorders provides important insights into basic biology and, in the case of DBA, ribosome biology; the disruption of which characterizes the disorder. Thus DBA serves as a paradigm for translational medicine in which the efforts of clinicians to manage DBA have informed laboratory scientists who, in turn, have stimulated clinical researchers to utilize scientific discovery to provide improved care. In this review we describe the clinical syndrome Diamond Blackfan Anemia and, in particular, we demonstrate how the study of DBA has allowed scientific inquiry to create opportunities for progress in its understanding and treatment.

  • Clinical utility gene card for: Diamond Blackfan Anemia
    European Journal of Human Genetics, 2011
    Co-Authors: Adrianna Vlachos, Irma Dianzani, Niklas Dahl, Jeffrey M. Lipton
    Abstract:

    European Journal of Human Genetics advance online publication, 19 January 2011; doi:10.1038/ejhg.2010.2471. DISEASE CHARACTERISTICS1.1 Name of the disease (synonyms)Diamond Blackfan Anemia, DBA1, 3–10 (DBA2 not confirmed), AaseSmith syndrome, congenital hypoplastic Anemia, Blackfan DiamondAnemia and inherited erythroblastopenia.1.2 OMIM# of the disease105650, 610629, 612527, 612528, 612561,612562, 612563, 613308 and613309.1.3 Name of the analysed genes or DNA/chromosome segmentsRPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10 andRPS26.1.4 OMIM# of the gene(s)603474, 602412, 180472, 180468, 603634, 604175, 603658, 603632 and603701.1.5 Mutational spectrumIn patients for whom there is a known mutation (50–60%), DiamondBlackfan Anemia results from a ribosomal protein haploinsufficiency.

  • Clinical utility gene card for: Diamond Blackfan Anemia
    European Journal of Human Genetics, 2011
    Co-Authors: Adrianna Vlachos, Irma Dianzani, Niklas Dahl, Jeffrey M. Lipton
    Abstract:

    European Journal of Human Genetics advance online publication, 19 January 2011; doi:10.1038/ejhg.2010.2471. DISEASE CHARACTERISTICS1.1 Name of the disease (synonyms)Diamond Blackfan Anemia, DBA1, 3–10 (DBA2 not confirmed), AaseSmith syndrome, congenital hypoplastic Anemia, Blackfan DiamondAnemia and inherited erythroblastopenia.1.2 OMIM# of the disease105650, 610629, 612527, 612528, 612561,612562, 612563, 613308 and613309.1.3 Name of the analysed genes or DNA/chromosome segmentsRPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10 andRPS26.1.4 OMIM# of the gene(s)603474, 602412, 180472, 180468, 603634, 604175, 603658, 603632 and603701.1.5 Mutational spectrumIn patients for whom there is a known mutation (50–60%), DiamondBlackfan Anemia results from a ribosomal protein haploinsufficiency.

Ugo Ramenghi - One of the best experts on this subject based on the ideXlab platform.

  • High frequency of ribosomal protein gene deletions in Italian Diamond-Blackfan Anemia patients detected by multiplex ligation-dependent probe amplification assay
    Haematologica, 2012
    Co-Authors: Paola Quarello, Irma Dianzani, Emanuela Garelli, Adriana Carando, Alfredo Brusco, Luciana Vinti, Cecilia Mancini, Patrizia Pappi, Johanna Svahn, Ugo Ramenghi
    Abstract:

    Diamond-Blackfan Anemia is an autosomal dominant disease due to mutations in nine ribosomal protein encoding genes. Because most mutations are loss of function and detected by direct sequencing of coding exons, we reasoned that part of the approximately 50% mutation negative patients may have carried a copy number variant of ribosomal protein genes. As a proof of concept, we designed a multiplex ligation-dependent probe amplification assay targeted to screen the six genes that are most frequently mutated in Diamond-Blackfan Anemia patients: RPS17, RPS19, RPS26, RPL5, RPL11, and RPL35A. Using this assay we showed that deletions represent approximately 20% of all mutations. The combination of sequencing and multiplex ligation-dependent probe amplification analysis of these six genes allows the genetic characterization of approximately 65% of patients, showing that Diamond-Blackfan Anemia is indisputably a ribosomopathy.

  • a new database for ribosomal protein genes which are mutated in diamond blackfan Anemia
    Human Mutation, 2008
    Co-Authors: Ilenia Boria, Irma Dianzani, Paola Quarello, Emanuela Garelli, Adriana Carando, Anna Aspesi, Maria Francesca Campagnoli, Federica Avondo, Ugo Ramenghi
    Abstract:

    Mutations in ribosomal proteins RPS19, RPS24 and RPS17 have been reported in Diamond-Blackfan Anemia (DBA), an autosomal dominant disease characterised by pure red cell aplasia. DBA is the prototype of ribosomapathies: a protein synthesis defect in a tissue with a high cellular turnover is considered the cause of the erythroid progenitor failure. We have created the Diamond-Blackfan Anemia mutation database to curate and record DBA gene mutations, together with their functional consequences and clinical phenotypes. This locus-specific resource is open to future submissions and is available online (http://www.dbagenes.unito.it). It is founded on the Leiden Open (source) Variation Database (LOVD) system and includes data from sequence and structure analysis tools, genomic database resources and published reports. It lists all identified variants and background genomic information. Phenotypic data are accessed by selecting a particular mutation. The database includes 219 unique variants of which 86 are disease-causing mutations. The database will be supplemented with other DBA genes as soon as they are reported and their mutations are identified and it should be of assistance to clinicians and investigators involved in DBA research and care. © 2008 Wiley-Liss, Inc.

  • Multiplex ligation-dependent probe amplification enhances molecular diagnosis of Diamond-Blackfan Anemia due to RPS19 deficiency.
    Haematologica, 2008
    Co-Authors: Paola Quarello, Irma Dianzani, Emanuela Garelli, Adriana Carando, Alfredo Brusco, Patrizia Pappi, Marco Barberis, Valentina Coletti, Maria Francesca Campagnoli, Ugo Ramenghi
    Abstract:

    Diamond-Blackfan Anemia (DBA,#MIM105650) is a rare congenital pure red cell aplasia characterized by nor-mochromic macrocytic Anemia, reticulocytopenia, and normocellular bone marrow with a selective deficiency of erythroid precursors. Defects in the RPS19 gene on chromosome 19q13.2 are the main

  • A new database for ribosomal protein genes which are mutated in Diamond-Blackfan Anemia.
    Human mutation, 2008
    Co-Authors: Ilenia Boria, Irma Dianzani, Paola Quarello, Emanuela Garelli, Adriana Carando, Anna Aspesi, Maria Francesca Campagnoli, Federica Avondo, Ugo Ramenghi
    Abstract:

    Mutations in ribosomal proteins RPS19, RPS24 and RPS17 have been reported in Diamond-Blackfan Anemia (DBA), an autosomal dominant disease characterised by pure red cell aplasia. DBA is the prototype of ribosomapathies: a protein synthesis defect in a tissue with a high cellular turnover is considered the cause of the erythroid progenitor failure. We have created the Diamond-Blackfan Anemia mutation database to curate and record DBA gene mutations, together with their functional consequences and clinical phenotypes. This locus-specific resource is open to future submissions and is available online (http://www.dbagenes.unito.it). It is founded on the Leiden Open (source) Variation Database (LOVD) system and includes data from sequence and structure analysis tools, genomic database resources and published reports. It lists all identified variants and background genomic information. Phenotypic data are accessed by selecting a particular mutation. The database includes 219 unique variants of which 86 are disease-causing mutations. The database will be supplemented with other DBA genes as soon as they are reported and their mutations are identified and it should be of assistance to clinicians and investigators involved in DBA research and care.

Paola Quarello - One of the best experts on this subject based on the ideXlab platform.

  • High frequency of ribosomal protein gene deletions in Italian Diamond-Blackfan Anemia patients detected by multiplex ligation-dependent probe amplification assay
    Haematologica, 2012
    Co-Authors: Paola Quarello, Irma Dianzani, Emanuela Garelli, Adriana Carando, Alfredo Brusco, Luciana Vinti, Cecilia Mancini, Patrizia Pappi, Johanna Svahn, Ugo Ramenghi
    Abstract:

    Diamond-Blackfan Anemia is an autosomal dominant disease due to mutations in nine ribosomal protein encoding genes. Because most mutations are loss of function and detected by direct sequencing of coding exons, we reasoned that part of the approximately 50% mutation negative patients may have carried a copy number variant of ribosomal protein genes. As a proof of concept, we designed a multiplex ligation-dependent probe amplification assay targeted to screen the six genes that are most frequently mutated in Diamond-Blackfan Anemia patients: RPS17, RPS19, RPS26, RPL5, RPL11, and RPL35A. Using this assay we showed that deletions represent approximately 20% of all mutations. The combination of sequencing and multiplex ligation-dependent probe amplification analysis of these six genes allows the genetic characterization of approximately 65% of patients, showing that Diamond-Blackfan Anemia is indisputably a ribosomopathy.

  • The spectrum of non-classical Diamond-Blackfan Anemia: a case of late beginning transfusion dependency associated to a new RPL5 mutation.
    Pediatric reports, 2012
    Co-Authors: Piero Farruggia, Paola Quarello, Emanuela Garelli, Olivia Paolicchi, Giovanni Battista Ruffo, Liana Cuccia, Sonia Cannella, Giuseppa Bruno, Paolo D'angelo
    Abstract:

    Diamond Blackfan Anemia typically presents in infants and is often associated with many kinds of malformations. Severity of Anemia often needs transfusional support in the first months of life. We describe here a patient with Diamond Blackfan Anemia related to a RPL5 mutation. The patient had no physical abnormalities and experienced a very late onset of transfusion dependency.

  • Diamond-Blackfan Anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations.
    Haematologica, 2009
    Co-Authors: Paola Quarello, Emanuela Garelli, Adriana Carando, Alfredo Brusco, Roberto Calabrese, Carlo Dufour, Daniela Longoni, Aldo Misuraca, Luciana Vinti, Anna Aspesi
    Abstract:

    Background Diamond-Blackfan Anemia is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors. About 40% of patients display various malformations. Anemia is corrected by steroid treatment in more than 50% of cases; non-responders need chronic transfusions or stem cell transplantation. Defects in the RPS19 gene, encoding the ribosomal protein S19, are the main known cause of Diamond-Blackfan Anemia and account for more than 25% of cases. Mutations in RPS24 , RPS17 , and RPL35A described in a minority of patients show that Diamond-Blackfan Anemia is a disorder of ribosome biogenesis. Two new genes ( RPL5 , RPL11 ), encoding for ribosomal proteins of the large subunit, have been reported to be involved in a considerable percentage of patients. Design and Methods In this genotype-phenotype analysis we screened the coding sequence and intron-exon boundaries of RPS14 , RPS16 , RPS24 , RPL5 , RPL11 , and RPL35A in 92 Italian patients with Diamond-Blackfan Anemia who were negative for RPS19 mutations. Results About 20% of the patients screened had mutations in RPL5 or RPL11 , and only 1.6% in RPS24 . All but three mutations that we report here are new mutations. No mutations were found in RPS14 , RPS16 , or RPL35A . Remarkably, we observed a higher percentage of somatic malformations in patients with RPL5 and RPL11 mutations. A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations. Conclusions Mutations in four ribosomal proteins account for around 50% of all cases of Diamond-Blackfan Anemia in Italian patients. Genotype-phenotype data suggest that mutation screening should begin with RPL5 and RPL11 in patients with Diamond-Blackfan Anemia with malformations.

  • a new database for ribosomal protein genes which are mutated in diamond blackfan Anemia
    Human Mutation, 2008
    Co-Authors: Ilenia Boria, Irma Dianzani, Paola Quarello, Emanuela Garelli, Adriana Carando, Anna Aspesi, Maria Francesca Campagnoli, Federica Avondo, Ugo Ramenghi
    Abstract:

    Mutations in ribosomal proteins RPS19, RPS24 and RPS17 have been reported in Diamond-Blackfan Anemia (DBA), an autosomal dominant disease characterised by pure red cell aplasia. DBA is the prototype of ribosomapathies: a protein synthesis defect in a tissue with a high cellular turnover is considered the cause of the erythroid progenitor failure. We have created the Diamond-Blackfan Anemia mutation database to curate and record DBA gene mutations, together with their functional consequences and clinical phenotypes. This locus-specific resource is open to future submissions and is available online (http://www.dbagenes.unito.it). It is founded on the Leiden Open (source) Variation Database (LOVD) system and includes data from sequence and structure analysis tools, genomic database resources and published reports. It lists all identified variants and background genomic information. Phenotypic data are accessed by selecting a particular mutation. The database includes 219 unique variants of which 86 are disease-causing mutations. The database will be supplemented with other DBA genes as soon as they are reported and their mutations are identified and it should be of assistance to clinicians and investigators involved in DBA research and care. © 2008 Wiley-Liss, Inc.

  • Multiplex ligation-dependent probe amplification enhances molecular diagnosis of Diamond-Blackfan Anemia due to RPS19 deficiency.
    Haematologica, 2008
    Co-Authors: Paola Quarello, Irma Dianzani, Emanuela Garelli, Adriana Carando, Alfredo Brusco, Patrizia Pappi, Marco Barberis, Valentina Coletti, Maria Francesca Campagnoli, Ugo Ramenghi
    Abstract:

    Diamond-Blackfan Anemia (DBA,#MIM105650) is a rare congenital pure red cell aplasia characterized by nor-mochromic macrocytic Anemia, reticulocytopenia, and normocellular bone marrow with a selective deficiency of erythroid precursors. Defects in the RPS19 gene on chromosome 19q13.2 are the main

Steven R Ellis - One of the best experts on this subject based on the ideXlab platform.

  • Nucleolar stress in Diamond Blackfan Anemia pathophysiology.
    Biochimica et biophysica acta, 2014
    Co-Authors: Steven R Ellis
    Abstract:

    Diamond Blackfan Anemia is a red cell hypoplasia that typically presents within the first year of life. Most cases of Diamond Blackfan Anemia are caused by ribosome assembly defects linked to haploinsufficiency for structural proteins of either ribosomal subunit. Nucleolar stress associated with abortive ribosome assembly leads to p53 activation via the interaction of free ribosomal proteins with HDM2, a negative regulator of p53. Significant challenges remain in linking this nucleolar stress signaling pathway to the clinical features of Diamond Blackfan Anemia. Defining aspects of disease presentation may relate to developmental and physiological triggers that work in conjunction with nucleolar stress signaling to heighten the p53 response in the developing erythron after birth. The growing number of ribosomopathies provides additional challenges for linking molecular mechanisms with clinical phenotypes. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.

  • Distinct ribosome maturation defects in yeast models of Diamond Blackfan Anemia and Shwachman Diamond syndrome
    Haematologica, 2009
    Co-Authors: Joseph B. Moore, Jason E. Farrar, Robert J. Arceci, Steven R Ellis
    Abstract:

    Background Diamond-Blackfan Anemia and Shwachman-Diamond syndrome are inherited bone marrow failure syndromes linked to defects in ribosome synthesis. The purpose of this study was to determine whether yeast models for Diamond-Blackfan Anemia and Shwachman-Diamond syndrome differed in the mechanism by which ribosome synthesis was affected. Design and Methods Northern blotting, pulse-chase analysis, and polysome profiling were used to study ribosome synthesis in yeast models. Localization of 60S ribosomal subunits was assessed using RPL25eGFP. Results Relative to wild-type controls, each disease model showed defects in 60S subunit maturation, but with distinct underlying mechanisms. In the model of Diamond-Blackfan Anemia, 60S subunit maturation was disrupted at a relatively early stage with abortive complexes subject to rapid degradation. 5S ribosomal RNA, unlike other large subunit ribosomal RNA in this model, accumulated as an extra-ribosomal species. In contrast, subunit maturation in the Shwachman-Diamond syndrome model was affected at a later step, giving rise to relatively stable pre-60S particles with associated 5S ribosomal RNA retained in the nucleus. Conclusions These differences between the yeast Diamond-Blackfan Anemia and Shwachman-Diamond syndrome models have implications for signaling mechanisms linking abortive ribosome assembly to cell fate decisions and may contribute to the divergent clinical presentations of Diamond-Blackfan Anemia and Shwachman-Diamond syndrome.

  • Diamond-Blackfan Anemia: Diagnosis,Treatment, and Molecular Pathogenesis
    Hematology oncology clinics of North America, 2009
    Co-Authors: Jeffrey M. Lipton, Steven R Ellis
    Abstract:

    Diamond-Blackfan Anemia (DBA) is a genetically and clinically heterogeneous disorder characterized by erythroid failure, congenital anomalies, and a predisposition to cancer. Faulty ribosome biogenesis, resulting in proapoptotic erythropoiesis leading to erythroid failure, is hypothesized to be the underlying defect. The genes identified to date that are mutated in DBA all encode ribosomal proteins associated with either the small or large subunit and in these cases haploinsufficiency gives rise to the disease. Extraordinarily robust laboratory and clinical investigations have recently led to demonstrable improvements in clinical care for patients with DBA.

  • Diamond Blackfan Anemia: A paradigm for a ribosome-based disease.
    Medical hypotheses, 2005
    Co-Authors: Steven R Ellis, Amy Tabb Massey
    Abstract:

    Diamond Blackfan Anemia is characterized by a severe hypoplastic Anemia and a heterogeneous collection of other clinical features. Approximately 25% of Diamond Blackfan Anemia cases are associated with mutations in the gene encoding ribosomal protein S19. The hypothesis presented here ties together molecular and clinical features of the disease, and establishes a conceptual framework for understanding many of the unusual characteristics of a growing number of diseases linked to factors involved in ribosome synthesis. The hypothesis states that ribosomal proteins are expressed in amounts that differ relative to one another in a tissue-specific manner, and that haploinsufficiency for a particular protein may make that protein limiting for ribosome assembly in some tissues, while other tissues remain unaffected. Further, polymorphisms in factors controlling the expression of a particular ribosomal protein gene may alter its expression and expand or contract the number of tissues affected from individual to individual. Support for the hypothesis comes from the observation that promoters in ribosomal protein genes exhibit little conservation and transcription profiling indicates that the absolute amounts of mRNAs for individual ribosomal proteins can vary dramatically relative to one another. Balanced expression of ribosomal proteins is achieved post-translationally, where excess proteins not assembled into ribosomal subunits are often rapidly degraded. The number of ribosomes per cell is therefore determined by the factors that limit assembly. In principle, any essential ribosomal protein could become limiting for assembly if its level of expression falls below a critical threshold. Whether an inactivating mutation in ribosomal protein gene would affect protein synthetic capacity of a tissue would depend on the ratio of the ribosomal protein relative to other ribosomal proteins in that tissue. If the ratio were high, the tissue may not be affected as the level of functional protein may not fall to a point where it becomes limiting for subunit assembly. In contrast, if the ratio were low, an inactivating mutation could make the protein limiting for subunit assembly resulting in a clinical phenotype. Polymorphisms in the myriad of cis- and trans-acting factors, which govern the expression of ribosomal proteins in response to developmental and physiological signals, could act to increase or decrease ribosomal protein expression and thereby impact the profile and severity of clinical phenotypes. Therefore, these factors represent targets for the development of new therapies to treat Diamond Blackfan Anemia and other ribosome based diseases.

  • Specific Role for Yeast Homologs of the Diamond Blackfan Anemia-associated Rps19 Protein in Ribosome Synthesis
    The Journal of biological chemistry, 2005
    Co-Authors: Isabelle Léger-silvestre, Jacqueline M. Caffrey, Rosie Dawaliby, Diana Alehandrovna Alvarez-arias, Nicole Gas, Salvatore J. Bertolone, Pierre-emmanuel Gleizes, Steven R Ellis
    Abstract:

    Approximately 25% of cases of Diamond Blackfan Anemia, a severe hypoplastic Anemia, are linked to heterozygous mutations in the gene encoding ribosomal protein S19 that result in haploinsufficiency for this protein. Here we show that deletion of either of the two genes encoding Rps19 in yeast severely affects the production of 40 S ribosomal subunits. Rps19 is an essential protein that is strictly required for maturation of the 3'-end of 18 S rRNA. Depletion of Rps19 results in the accumulation of aberrant pre-40 S particles retained in the nucleus that fail to associate with pre-ribosomal factors involved in late maturation steps, including Enp1, Tsr1, and Rio2. When introduced in yeast Rps19, amino acid substitutions found in Diamond Blackfan Anemia patients induce defects in the processing of the pre-rRNA similar to those observed in cells under-expressing Rps19. These results uncover a pivotal role of Rps19 in the assembly and maturation of the pre-40 S particles and demonstrate for the first time the effect of Diamond Blackfan Anemia-associated mutations on the function of Rps19, strongly connecting the pathology to ribosome biogenesis.