Edyta Niewiadomska

Publications (8)52.33 Total impact

• Article: Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond-blackfan anemia.

  Hanna T Gazda, Milena Preti, Mee Rie Sheen, Marie-Françoise O'Donohue, Adrianna Vlachos, Stella M Davies, Antonis Kattamis, Leana Doherty, Michael Landowski, Christopher Buros, Roxanne Ghazvinian, Colin A Sieff, Peter E Newburger, Edyta Niewiadomska, Michal Matysiak, Bertil Glader, Eva Atsidaftos, Jeffrey M Lipton, Pierre-Emmanuel Gleizes, Alan H Beggs
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  ABSTRACT: Diamond-Blackfan anemia (DBA) is an inherited form of pure red cell aplasia that usually presents in infancy or early childhood and is associated with congenital malformations in ∼30-50% of patients. DBA has been associated with mutations in nine ribosomal protein (RP) genes in about 53% of patients. We completed a large-scale screen of 79 RP genes by sequencing 16 RP genes (RPL3, RPL7, RPL8, RPL10, RPL14, RPL17, RPL19, RPL23A, RPL26, RPL27, RPL35, RPL36A, RPL39, RPS4X, RPS4Y1, and RPS21) in 96 DBA probands. We identified a de novo two-nucleotide deletion in RPL26 in one proband associated with multiple severe physical abnormalities. This mutation gives rise to a remarkable ribosome biogenesis defect that affects maturation of both the small and the large subunits. We also found a deletion in RPL19 and missense mutations in RPL3 and RPL23A, which may be variants of unknown significance. Together with RPL5, RPL11, and RPS7, RPL26 is the fourth RP regulating p53 activity that is linked to DBA.
  Human Mutation 03/2012; 33(7):1037-44. · 5.69 Impact Factor
• Article: Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia.

  Leana Doherty, Mee Rie Sheen, Adrianna Vlachos, Valerie Choesmel, Marie-Françoise O'Donohue, Catherine Clinton, Hal E Schneider, Colin A Sieff, Peter E Newburger, Sarah E Ball, Edyta Niewiadomska, Michal Matysiak, Bertil Glader, Robert J Arceci, Jason E Farrar, Eva Atsidaftos, Jeffrey M Lipton, Pierre-Emmanuel Gleizes, Hanna T Gazda
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  ABSTRACT: Diamond-Blackfan anemia (DBA), an inherited bone marrow failure syndrome characterized by anemia that usually presents before the first birthday or in early childhood, is associated with birth defects and an increased risk of cancer. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart, and urinary system defects that are present in approximately 30%-50% of patients. DBA has been associated with mutations in seven ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7, in about 43% of patients. To continue our large-scale screen of RP genes in a DBA population, we sequenced 35 ribosomal protein genes, RPL15, RPL24, RPL29, RPL32, RPL34, RPL9, RPL37, RPS14, RPS23, RPL10A, RPS10, RPS12, RPS18, RPL30, RPS20, RPL12, RPL7A, RPS6, RPL27A, RPLP2, RPS25, RPS3, RPL41, RPL6, RPLP0, RPS26, RPL21, RPL36AL, RPS29, RPL4, RPLP1, RPL13, RPS15A, RPS2, and RPL38, in our DBA patient cohort of 117 probands. We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands. Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knockdown of RPS10 or RPS26 expression with siRNAs, which indicates that mutations in the RPS10 and RPS26 genes in DBA patients affect the function of the proteins in rRNA processing.
  The American Journal of Human Genetics 02/2010; 86(2):222-8. · 10.60 Impact Factor
• Article: Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients.

  Hanna T Gazda, Mee Rie Sheen, Adrianna Vlachos, Valerie Choesmel, Marie-Françoise O'Donohue, Hal Schneider, Natasha Darras, Catherine Hasman, Colin A Sieff, Peter E Newburger, [......], Edyta Niewiadomska, Michal Matysiak, Jan M Zaucha, Bertil Glader, Charlotte Niemeyer, Joerg J Meerpohl, Eva Atsidaftos, Jeffrey M Lipton, Pierre-Emmanuel Gleizes, Alan H Beggs
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  ABSTRACT: Diamond-Blackfan anemia (DBA), a congenital bone-marrow-failure syndrome, is characterized by red blood cell aplasia, macrocytic anemia, clinical heterogeneity, and increased risk of malignancy. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital anomalies that are present in approximately 30%-50% of patients. The disease has been associated with mutations in four ribosomal protein (RP) genes, RPS19, RPS24, RPS17, and RPL35A, in about 30% of patients. However, the genetic basis of the remaining 70% of cases is still unknown. Here, we report the second known mutation in RPS17 and probable pathogenic mutations in three more RP genes, RPL5, RPL11, and RPS7. In addition, we identified rare variants of unknown significance in three other genes, RPL36, RPS15, and RPS27A. Remarkably, careful review of the clinical data showed that mutations in RPL5 are associated with multiple physical abnormalities, including craniofacial, thumb, and heart anomalies, whereas isolated thumb malformations are predominantly present in patients carrying mutations in RPL11. We also demonstrate that mutations of RPL5, RPL11, or RPS7 in DBA cells is associated with diverse defects in the maturation of ribosomal RNAs in the large or the small ribosomal subunit production pathway, expanding the repertoire of ribosomal RNA processing defects associated with DBA.
  The American Journal of Human Genetics 01/2009; 83(6):769-80. · 10.60 Impact Factor
• Article: Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia.

  Jason E Farrar, Michelle Nater, Emi Caywood, Michael A McDevitt, Jeanne Kowalski, Clifford M Takemoto, C Conover Talbot, Paul Meltzer, Diane Esposito, Alan H Beggs, [......], Agnieszka Grabowska, Sarah E Ball, Edyta Niewiadomska, Colin A Sieff, Adrianna Vlachos, Eva Atsidaftos, Steven R Ellis, Jeffrey M Lipton, Hanna T Gazda, Robert J Arceci
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  ABSTRACT: Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, congenital abnormalities, and cancer predisposition. Small ribosomal subunit genes RPS19, RPS24, and RPS17 are mutated in approximately one-third of patients. We used a candidate gene strategy combining high-resolution genomic mapping and gene expression microarray in the analysis of 2 DBA patients with chromosome 3q deletions to identify RPL35A as a potential DBA gene. Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA. shRNA inhibition shows that Rpl35a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival. Analysis of pre-rRNA processing in primary DBA lymphoblastoid cell lines demonstrated similar alterations of large ribosomal subunit rRNA in both RPL35A-mutated and some RPL35A wild-type patients, suggesting additional large ribosomal subunit gene defects are likely present in some cases of DBA. These data demonstrate that alterations of large ribosomal subunit proteins cause DBA and support the hypothesis that DBA is primarily the result of altered ribosomal function. The results also establish that haploinsufficiency of large ribosomal subunit proteins contributes to bone marrow failure and potentially cancer predisposition.
  Blood 07/2008; 112(5):1582-92. · 9.90 Impact Factor
• Article: [Results of immunosupressive therapy in children with severe aplastic anaemia. Report of the Polish Paediatric Haematology Group].

  Katarzyna Pawelec, Michał Matysiak, Edyta Niewiadomska, Roma Rokicka-Milewska, Jerzy Kowalczyk, Jolanta Stefaniak, Walentyna Balwierz, Ewa Załecka-Czerpko, Alicja Chybicka, Krzysztof Szmyd, [......], Jacek Wachowiak, Grzegorz Grund, Wojciech Młynarski, Monika Bulas, Maryna Krawczuk-Rybak, Elzbieta Leszczyńska, Tomasz Urasiński, Jarosław Peregud-Pogorzelski, Anna Balcerska, Marek Włazłowski
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  ABSTRACT: Bone marrow transplantation from HLA identical family donors is the treatment of choice for children with severe aplastic anaemia (SAA). When there is no donor available, combined immunosuppressive therapy is given. evaluation of results of immunosupressive therapy in children with severe aplastic anaemia. Material and methods: SAA was diagnosed in 105 children (42 girls, 73 boys), aged 2-18 years, in the eleven haematological centres in Poland, between 1993-2007. All patients received the Severe Aplastic Anaemia Working Party of the EBMT protocol which included: antilymphocyte globulin or antithymocyte globulin, cyclosporin A, prednisolone. Granulocyto- or granulocytomacrophagic-cell stimulation factor was additionally administered during deep neutropenia. Haematological response was evaluated on day 84 or 112 and 180 of the therapy. complete remission occurred in 53 patients (51.5%), partial remission in 27 (24.7%), no response was obtained in 25 children (23.8%) on day 180, of the therapy. Period of observation was from 12 months to 12.5 years. During this time relapse occurred in 10 patients (9.5%). We observed 22 deaths: 8 early, during the first 3 months of IS and 14 after the first 3 months of immunosuppresive therapy (IS). At present 70 children (66.6%) are in first remission with lasts from 12 months to 12.5 years. The survival at 12.5-years is 78.6%. During the 12.5 years of follow-up we had two cases with a late clonal complication (PNH and MDS). Transformation to acute nonlymphoblastic leukaemia was observed in two of our patients. 1. Immunosuppresive therapy (IS) in children with SAA, without bone marrow family donors, is more effective after introduction of combined IS (12.5 years survival in this study was 80% for children with very severe aplastic anaemia (v SAA). 2. In our studies among the children followed up after IS therapy, there were: 1 case of periodic nocturnal haemoglobinuria (PNH), 1 case of myelodysplastic syndrome (MDS) and 2 cases of myeloid leukaemia (probability of incidence was 3.8%).
  Medycyna wieku rozwojowego 02/2008; 12(4 Pt 2):1092-7.
• Article: Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia.

  Hanna T Gazda, Agnieszka Grabowska, Lilia B Merida-Long, Elzbieta Latawiec, Hal E Schneider, Jeffrey M Lipton, Adrianna Vlachos, Eva Atsidaftos, Sarah E Ball, Karen A Orfali, [......], Charlotte Niemeyer, Joerg J Meerpohl, Joachim Stahl, Gerhard Schratt, Bertil Glader, Karen Backer, Carolyn Wong, David G Nathan, Alan H Beggs, Colin A Sieff
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  ABSTRACT: Diamond-Blackfan anemia (DBA) is a rare congenital red-cell aplasia characterized by anemia, bone-marrow erythroblastopenia, and congenital anomalies and is associated with heterozygous mutations in the ribosomal protein (RP) S19 gene (RPS19) in approximately 25% of probands. We report identification of de novo nonsense and splice-site mutations in another RP, RPS24 (encoded by RPS24 [10q22-q23]) in approximately 2% of RPS19 mutation-negative probands. This finding strongly suggests that DBA is a disorder of ribosome synthesis and that mutations in other RP or associated genes that lead to disrupted ribosomal biogenesis and/or function may also cause DBA.
  The American Journal of Human Genetics 01/2007; 79(6):1110-8. · 10.60 Impact Factor
• Article: RNA and protein evidence for haplo-insufficiency in Diamond-Blackfan anaemia patients with RPS19 mutations.

  Hanna T Gazda, Rong Zhong, Lilia Long, Edyta Niewiadomska, Jeffrey M Lipton, Anna Ploszynska, Jan M Zaucha, Adrianna Vlachos, Evangelia Atsidaftos, David H Viskochil, Charlotte M Niemeyer, Joerg J Meerpohl, Roma Rokicka-Milewska, Dagmar Pospisilova, W Wiktor-Jedrzejczak, David G Nathan, Alan H Beggs, Colin A Sieff
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  ABSTRACT: The genetic basis of Diamond-Blackfan anaemia (DBA), a congenital erythroid hypoplasia that shows marked clinical heterogeneity, remains obscure. However, the fact that nearly one-quarter of patients harbour a variety of mutations in RPS19, a ribosomal protein gene, provides an opportunity to examine whether haplo-insufficiency of RPS19 protein can be demonstrated in certain cases. To that end, we identified 19 of 81 DBA index cases, both familial and sporadic, with RPS19 mutations. We found 14 distinct insertions, deletions, missense, nonsense and splice site mutations in the 19 probands, and studied mutations in 10 patients at the RNA level and in three patients at the protein level. Characterization of the mutations in 10 probands, including six with novel insertions, nonsense and splice site mutations, showed that the abnormal transcript was detectable in nine cases. The RPS19 mRNA and protein in CD34+ bone marrow cells identified haplo-insufficiency in three cases predicted to have one functional allele. Our data support the notion that, in addition to rare DBA patients with the deletion of one allele, the disease in certain other RPS19 mutant patients is because of RPS19 protein haplo-insufficiency.
  British Journal of Haematology 11/2004; 127(1):105-13. · 4.94 Impact Factor
• Article: [Results of immunosuppressive therapy in children with severe aplastic anaemia. Report by the Polish Paediatric Leukaemia and Lymphoma Study Group].

  Katarzyna Pawelec, Michał Matysiak, Edyta Niewiadomska, Roma Rokicka-Milewska, Jerzy Kowalczyk, Jolanta Stefaniak, Walentyna Balwierz, Ewa Załecka-Czepko, Alicja Chybicka, Krzysztof Szmyd, [......], Jacek Wachowiak, Małgorzata Kaczmarek-Kanold, Małgorzata Stolarska, Izabela Karolczyk, Maryna Krawczuk-Rybak, Elzbieta Leszczyńska, Tomasz Urasiński, Jarosław Peregud-Pogorzelski, Anna Balcerska, Marek Włazłowski
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  ABSTRACT: Bone marrow transplantation from HLA identical family donors is the treatment of choice for children with severe aplastic anaemia (SAA). When no donor is available, combined immunosuppressive therapy is given. Evaluation of results of immunosuppressive therapy in children with severe aplastic anaemia. SAA was diagnosed in 85 children (31 girls, 54 boys) aged 2-17.5 years in the eleven centres of the Polish Paediatric Leukaemia and Lymphoma Study Group (PPLLSG) in Poland between 1993-2003 years. All patients received protocol of the Severe Aplastic Anaemia Working Party of the Europe Bone Marrow Transplant (EBMT): antilymphocyte globulin or antithymocyte globulin, cyclosporin A, prednisolone and granulocyto- or granulocyto-macrophagic-cell stimulation factor was additionally administered during deep neutropenia. Haematological response was evaluated on day 84, 112 or 180 of the therapy. complete remission occurred in 43 patients (50.5%), partial remission in 22 (25.4%), no response was obtained in 20 children (23.7%) in 180 day of the therapy. Period of observation was from 12 months to 10.5 years. During this time relapse occurred in 6 patients (7%). We observed 16 deaths: 7 early during the first 3 months of immunosuppressive therapy (IS) and 9 after the first 3 months of IS. Conclusion: the actual survival at 10-years, after immunosuppressive therapy is 81.2% in our group. Transformation to leukaemia or myelodysplastic syndrome (MDS) was not observed in any of our patients. We observed one case with paroxysmal nocturnal haemoglobinuria (PNH).
  Medycyna wieku rozwojowego 10(3 Pt 1):832-9.