Diamond-Blackfan Anemia: Report of Seven Further Mutations in the RPS19 Gene and Evidence of Mutation Heterogeneity in the Italian Population

Ramenghi, Ugo; Campagnoli, Maria Francesca; Garelli, Emanuela; Carando, Adriana; Brusco, Alfredo; Gp, Bagnara; Strippoli, Pierluigi; Izzi, Gc; Brandalise, Sílvia Regina; Riccardi, Riccardo; Dianzani, Irma

doi:10.1006/bcmd.2000.0324

Cited by 36 publications

(28 citation statements)

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“…Cases 30, 44 and 43 harbored the same RPS19 mutations reported in multicase families (p.R62Q, p.R62W, p.0). 6,10,11,[22][23][24][25][26][27] Comparable to previous observations, no consistent clinical features were found in patients from different families displaying mutations in RPS19. For example, the father of case 30 harboring the same mutation had no finger anomalies, although case 30 had syndactyly and thumb polydactyly.…”

Section: Genotype-phenotype Correlations: Congenital Anomaliesmentioning

confidence: 74%

“…Missense mutations resulting in amino acid substitutions were noted in four index cases. The three mutations, p.R62Q in case 30, p.R62W in case 44 and p.0 in case 43, have been reported in seven, ten and two families, respectively, 6,10,11,[22][23][24][25][26] whereas one mutation, p.G95V in case 25, was novel, and could not be found in the Single Polymorphism Database (dbSNP at www.ncbi.nlm.nih.gov/SNP). Furthermore, the mutation was not observed in DNA from 50 normal individuals.…”

Section: Rps19mentioning

confidence: 99%

“…[22][23][24]29 In Italian DBA patients, the risk of malformation was 7-fold higher in RPL5-mutated patients than in RPS19-mutated patients. 29 In contrast, all of the Japanese DBA patients with RPS19 mutations had one or more malformations.…”

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Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blackfan anemia

et al. 2010

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BackgroundDiamond-Blackfan anemia is a rare, clinically heterogeneous, congenital red cell aplasia: 40% of patients have congenital abnormalities. Recent studies have shown that in western countries, the disease is associated with heterozygous mutations in the ribosomal protein (RP) genes in about 50% of patients. There have been no studies to determine the incidence of these mutations in Asian patients with Diamond-Blackfan anemia. Design and MethodsWe screened 49 Japanese patients with Diamond-Blackfan anemia (45 probands) for mutations in the six known genes associated with Diamond-Blackfan anemia: RPS19, RPS24, RPS17, RPL5, RPL11, and RPL35A. RPS14 was also examined due to its implied involvement in 5q-syndrome. ResultsMutations in RPS19, RPL5, RPL11 and RPS17 were identified in five, four, two and one of the probands, respectively. In total, 12 (27%) of the Japanese Diamond-Blackfan anemia patients had mutations in ribosomal protein genes. No mutations were detected in RPS14, RPS24 or RPL35A. All patients with RPS19 and RPL5 mutations had physical abnormalities. Remarkably, cleft palate was seen in two patients with RPL5 mutations, and thumb anomalies were seen in six patients with an RPS19 or RPL5 mutation. In contrast, a small-for-date phenotype was seen in five patients without an RPL5 mutation. ConclusionsWe observed a slightly lower frequency of mutations in the ribosomal protein genes in patients with Diamond-Blackfan anemia compared to the frequency reported in western countries. Genotype-phenotype data suggest an association between anomalies and RPS19 mutations, and a negative association between small-for-date phenotype and RPL5 mutations.Key words: protein genes, Diamond-Blackfan anemia, RPL5 mutation. DiamondBlackfan anemia. Haematologica 2010;95(8):1293-1299. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Konno Y, Toki T, Tandai S, Xu G, Wang RN, Terui K, Ohga S, Hara T, Hama A, Kojima S, Hasegawa D, Kosaka Y, Yanagisawa R, Koike K, Kanai R, Imai T, Hongo T, Park M-J, Sugita K, and Ito E. Mutations in the ribosomal protein genes in Japanese patients with Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blackfan anemia

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Section: Genotype-phenotype Correlations: Congenital Anomaliesmentioning

confidence: 74%

Section: Rps19mentioning

confidence: 99%

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Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blackfan anemia

et al. 2010

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“…a, Draptchinskaia et al (1999);b, Willig et al (1999b); c, Ramenghi et al (2000); d, Cmejla et al (2000); e, Gazda et al (2004). saline (PBS), resuspended at 0AE5-2AE0 · 10 5 cells in 300 ll of 2 lg/ml Hoechst33342 and 1% BSA in PBS and incubated for 20 min at 37°C.…”

Section: Cell Cycle Analysismentioning

confidence: 99%

Deficient RPS19 protein production induces cell cycle arrest in erythroid progenitor cells

Kuramitsu¹,

Hamaguchi²,

Mizukami³

et al. 2008

Br J Haematol

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SummaryThe gene encoding ribosomal protein S19 (RPS19) is one of the responsible genes for Diamond-Blackfan anaemia (DBA), a congenital erythroblastopenia. Although haplo-insufficiency of RPS19 has been suggested to be the onset mechanism underlying the pathogenesis of DBA, the sequential mechanism has not been elucidated. In order to analyse the consequences of the missense mutation of RPS19 specific for DBA patients, we made mutated RPS19 expression vectors. Twelve C-terminally Flag-tagged missense mutants were exogenously expressed from retroviral vectors and analysed by Western blot analysis and flow cytometry. When these 12 mutants were expressed in the erythro-leukaemic cell lines K562 and human bone marrow CD34 + cells, almost all of the mutant proteins (except for G120R) were unstable, and the levels of mutated RPS19 protein were significantly low. To address the effect of deficient RPS19 expression on cell proliferation, RPS19 was downregulated by siRNA. Repressive expression of RPS19 in human CD34 + cells produced an elevated number of cells at G0 and induced erythroid progenitor-specific defects in BM cells. These results suggest that abnormal ribosomal biogenesis causes inadequate cell cycle arrest in haematopoietic progenitors, and that, subsequently, erythroid progenitors are specifically hampered. These in vitro phenotypes of genetically manipulated CD34 + cells mimic DBA pathogenesis.

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“…Ten percent to 15% of patients have other family members with DBA, and another 30% have a first-degree family member with either elevated eADA levels or elevated MCV, possibly reflecting familial disease with incomplete penetrance. 16,17 In families in which the DBA genotype is not characterized, relatives with elevated eADA and MCV may not be suitable as stem-cell donors because they possibly carry a silent DBA phenotype. 16 Approximately 25% have a mutation in the RPS19 gene (Figure 1), whereas only 2% appear to have a mutation in the RPS24 gene.…”

Section: Inheritance and Geneticsmentioning

confidence: 99%

Diamond-Blackfan anemia: erythropoiesis lost in translation

Flygare

Karlsson

2006

Blood

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Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents as macrocytic anemia during infancy. Linkage analysis suggests that at least 4 genes are associated with DBA of which 2 have been identified so far. The known DBA genes encode the ribosomal proteins S19 and S24 accounting for 25% and 2% of the patients, respectively. Herein, we review possible links between ribosomal proteins and erythropoiesis that might explain DBA pathogenesis. Recent studies and emerging findings suggest that a malfunctioning transla- IntroductionDiamond-Blackfan anemia (DBA) is categorized as a congenital hypoplastic anemia, presenting during infancy with normochromicmacrocytic anemia, reticulocytopenia, and low numbers of erythroid precursors in the bone marrow. In addition to anemia more than 50% of patients with DBA have a short stature and/or various physical abnormalities. 1 Already in 1938 L. K. Diamond and K. D. Blackfan discussed the cause of this bewildering disease and proposed: ". . .there may be congenital insufficiency of red marrow tissue and inability on the part of the hematopoietic system to respond to the need for more blood as the erythrocytes wear out." 2(p465) The pathogenetics causing DBA remained speculative until 1999 when a balanced reciprocal translocation t(X;19) was discovered in a patient, revealing the first DBA gene (DBA1). 3 The identification of the affected gene in a congenital disorder, such as DBA, is often the key that suddenly enables understanding of the molecular pathogenesis and development of novel therapies. Surprisingly, DBA1 was identified as ribosomal protein S19 (RPS19), not a regulator of erythropoiesis as might be expected but a ribosomal protein that is vastly expressed in all tissues. Recently, the identification of a second DBA gene has established DBA as a ribosomal disorder because the affected gene encodes ribosomal protein S24 (RPS24). 4 Herein, we review the major advances toward answering the question of how a deficiency of a ubiquitously expressed ribosomal protein can specifically affect erythroid development. Clinical features and current treatmentDBA is a congenital hypoplastic anemia that develops within the first year of life, often with pallor as the only initial symptom. Typical laboratory findings include decreased hemoglobin levels, elevated mean corpuscular volume (MCV), and reticulocytopenia. 5,6 Bone marrow examination reveals an isolated erythroid hypoplasia in normocellular marrow. Additional hematologic findings supporting the DBA diagnosis are elevated erythrocyte adenosine deaminase (eADA) activity, 7 elevated fetal hemoglobin, and elevated serum erythropoietin. Growth retardation and/or thumb, craniofacial, heart, or urogenital anomalies further support the DBA diagnosis. 1 Although not yet statistically validated, patients with DBA also seem to have an increased risk of acute myeloid leukemia (AML) and a wide variety of nonhematopoietic tumors, for example, osteogenic sarcomas. 1,[8][9][10] The main differential diagnosis is tra...

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Diamond-Blackfan Anemia: Report of Seven Further Mutations in the RPS19 Gene and Evidence of Mutation Heterogeneity in the Italian Population

Cited by 36 publications

References 16 publications

Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blackfan anemia

Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blackfan anemia

Deficient RPS19 protein production induces cell cycle arrest in erythroid progenitor cells

Diamond-Blackfan anemia: erythropoiesis lost in translation

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