Identification of proteins of the 40 S ribosomal subunit involved in interaction with initiation factor eIF‐2 in the quaternary initiation complex by means of monospecific antibodies

Bommer, Ulrich‐Axel; Stahl, Joachim; Henske, Annemarie; Lutsch, Gudrun; Bielka, H

doi:10.1016/0014-5793(88)81366-8

Cited by 27 publications

(19 citation statements)

References 11 publications

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“…3,4,6 We screened RPS16 because it is involved in binding of initiation factor eIF-2 to the 40S subunit. 11 The RPS14 gene was screened because it has an important role in erythroid proliferation and maturation.…”

Section: Molecular Analysis Of Rp Genesmentioning

confidence: 99%

Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations

Quarello¹,

Garelli²,

Carando³

et al. 2009

Haematologica

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BackgroundDiamond-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; nonresponders need chronic transfusions or stem cell transplantation. Defects in the RPS19 gene, encoding the ribosomal protein S19, are the main known cause of DiamondBlackfan 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 MethodsIn 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. ResultsAbout 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. ConclusionsMutations in four ribosomal proteins account for around 50% of all cases of DiamondBlackfan 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.Key words: red cells, bone marrow failure, anemia, DBA, ribosomal proteins.Citation: Quarello P, Garelli E, Carando A, Brusco A, Calabrese R, Dufour C, Longoni D, Misuraca A, Vinti L, Aspesi A, Biondini L, Loreni F, Dianzani I, and Ramenghi U. Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations Haematologica. 2010; 95:206-213. doi:10.3324/haematol.2009

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Section: Molecular Analysis Of Rp Genesmentioning

confidence: 99%

Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations

Quarello¹,

Garelli²,

Carando³

et al. 2009

Haematologica

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“…Immunoelectron microscope studies locate RPS19 to the external surface of the 40S subunit, 48 where it is in close vicinity to RPS3a, RPS13/16, and RPS24, a region that interacts with eIF-2 during ribosomal scanning and translation initiation. 49 RPS19 is a very conserved protein, and only a single amino acid has changed since rodents and primates diverged 100 million years ago. Two nontranscribed RPS19 pseudogenes are described in humans and one in mice.…”

Section: Ribosomes and Rps19mentioning

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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“…Beyond RMRP (pre-rRNA processing) in CHH, other genes/diseases linked to ribosomal biosynthesis include DKC1 (rRNA modification) in X-linked dyskeratosis congenital, RPS19 (40S ribosomal subunit maturation) in Diamond-Blackfan anemia, and SBDS (40S ribosomal subunit maturation) in Shwachman-Diamond syndrome. RPS19, one of the protein components of 40S small ribosomal subunit, is involved in the interaction of the 40S subunit and elongation factor 2 (eIF-2) [24]. A 5.8S rRNA mutant was demonstrated to substantially reduce the level of eIF-2 associated with polyribosomes [25].…”

Section: Chh-related Rna Metabolismmentioning

confidence: 99%

RNase MRP RNA and human genetic diseases

Martin

2006

Cell Res

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Identification of proteins of the 40 S ribosomal subunit involved in interaction with initiation factor eIF‐2 in the quaternary initiation complex by means of monospecific antibodies

Cited by 27 publications

References 11 publications

Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations

Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations

Diamond-Blackfan anemia: erythropoiesis lost in translation

RNase MRP RNA and human genetic diseases

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