Identification of mutations in the ribosomal protein L5 (RPL5) and ribosomal protein L11 (RPL11) genes in Czech patients with Diamond-Blackfan anemia

Čmejla, Radek; Čmejlová, Jana; Handrková, Helena; Petrák, Jir̆ı́; K, Petrtýlová; Mihál, Vladimı́r; Starý, Jan; Černá, Zuzana; Jabali, Yahia; Pospı́šilová, Dagmar

doi:10.1002/humu.20874

Cited by 92 publications

(94 citation statements)

References 23 publications

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“…This feedback regulation may also act as an intrinsic mechanism or surveillance for controlling cell transformation and tumorigenesis because defects of this pathway could lead to deregulated c-Myc activity and tumorigenesis. Recently, it was shown that haploinsufficiency of L11 and other ribosomal proteins, due to loss of function gene mutations or deletions, occurs in patients with Diamond-Blackfan anemia (27,28), an inherited disorder with bone marrow failure and increased incidence of cancer formation (29). It will be interesting to test if c-Myc activity is enhanced and contributes to cancer susceptibility in this disorder in the near future.…”

Section: Discussionmentioning

confidence: 99%

Ribosomal Protein L11 Associates with c-Myc at 5 S rRNA and tRNA Genes and Regulates Their Expression

Dai

Sun

2010

Journal of Biological Chemistry

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The c-Myc oncoprotein promotes cell growth by enhancing ribosomal biogenesis. Overexpression of c-Myc and aberrant ribosomal biogenesis lead to deregulated cell growth and tumorigenesis. Hence, c-Myc activity and ribosomal biogenesis must be tightly coordinated during normal homeostasis. We previously found that ribosomal protein L11 inhibits c-Myc activity by blocking the recruitment of its co-activator transformation/transcription domain-associated protein (TRRAP) to the promoter regions of c-Myc target genes that are transcribed by RNA polymerases I and II. In this study, we extended the role of L11 to the regulation of c-Myc-driven transcription of the 5 S rRNA and tRNA genes by RNA polymerase III. L11 co-resided with c-Myc at the 5 S rRNA and tRNA genes and significantly inhibited the binding of TRRAP to these genes. Knocking down endogenous L11 enhanced c-Myc-dependent transcription of these genes. Interestingly, in response to ribosomal stress induced by the treatment of cells with a low dose of actinomycin D or serum starvation, L11 binding to these genes was increased, and inversely TRRAP binding to these genes was decreased. Consistently, knockdown of L11 rescued the reduction of the expression of these genes by the two treatments. These results demonstrate that L11 suppresses c-Myc-dependent and RNA polymerase III-catalyzed transcription of 5 S rRNA and tRNA genes in response to ribosomal stress, ensuring a tight coordination between c-Myc activity and ribosomal biogenesis.

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Section: Discussionmentioning

confidence: 99%

Ribosomal Protein L11 Associates with c-Myc at 5 S rRNA and tRNA Genes and Regulates Their Expression

Dai

Sun

2010

Journal of Biological Chemistry

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“…[16][17][18][19] More recently, Gazda et al identified mutations in RPL5 and RPL11 in an additional 11.4% of patients and noted that mutations in RPL5 were associated with a higher frequency of physical abnormalities, including cleft lip and/or palate, whereas mutations in RPL11 had more isolated thumb abnormalities compared with patients with mutations in RPS19. 20 Subsequent work by the Czech DBA registry revealed that, in the 10 patients with either a RPL5 or RPL11 mutation, there was a thumb abnormality, whereas none 21 This may indicate that mutations in different ribosomal genes lead to distinct clinical phenotypes. A large-scale screen of RP genes in the DBA population has also revealed candidate mutations in RPS7, RPL36, RPS15, and RPS27A.…”

Section: Diamond-blackfan Anemiamentioning

confidence: 99%

“…by guest www.bloodjournal.org From of the 7 patients with RPS19 mutations in the registry exhibited such an anomaly. 21 This may indicate that mutations in different ribosomal genes lead to distinct clinical phenotypes. A large-scale screen of RP genes in the DBA population has also revealed candidate mutations in RPS7, RPL36, RPS15, and RPS27A.…”

Section: Diamond-blackfan Anemiamentioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

689

726

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Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, SchwachmanDiamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q؊ syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. Identification of ribosomal abnormalities in human diseaseIn 1999, Draptchinskaia et al reported recurrent mutations in a ribosomal protein gene, RPS19, in patients with Diamond-Blackfan anemia (DBA), a rare congenital bone marrow failure syndrome with a striking erythroid defect. 1 Since that initial discovery, mutations in a number of ribosomal proteins have been identified in up to 50% of patients with DBA. Moreover, other congenital syndromes have been linked to defective ribosome biogenesis, including Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DKC), cartilage hair hypoplasia (CHH), and Treacher Collins syndrome (TCS). 2 In the 5qϪ syndrome, a subtype of adult myelodysplastic syndrome, acquired haploinsufficiency for RPS14 resulting from an interstitial chromosomal deletion causes a severe refractory anemia. 3 Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure and/or craniofacial or other skeletal defects. The disorders of ribosome dysfunction have become collectively known as ribosomopathies. Overview of ribosome biogenesisThe eukaryotic ribosome is composed of 40S and 60S subunits, which associate to form the translationally active 80S ribosome. This process requires the coordinated synthesis of 4 ribosomal RNAs (rRNAs), approximately 80 core ribosomal proteins, more than 150 associated proteins, and approximately 70 small nucleolar RNAs (snoRNAs). 4,5 The 40S subunit contains 18S rRNA and the 60S subunit contains 28S, 5.8S, and 5S rRNAs. In eukaryotes, assembly of rRNA and ribosomal proteins, along with assoc...

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“…These genes encode for RP of either the small or the large ribosomal subunit. [3][4][5][6][7] The identification of the role of another RP gene, RPS14, in the pathogenesis of an acquired myelodysplastic disease, the 5q-syndrome, has recently attracted great interest, since it extends the spectrum of ribosomal diseases. 8 A clear genotype-phenotype correlation is not apparent in patients with RPS19 mutations, and identical mutations have been found in patients with a wide range of clinical presentations, even within the same family.…”

Section: Introductionmentioning

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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Identification of mutations in the ribosomal protein L5 (RPL5) and ribosomal protein L11 (RPL11) genes in Czech patients with Diamond-Blackfan anemia

Cited by 92 publications

References 23 publications

Ribosomal Protein L11 Associates with c-Myc at 5 S rRNA and tRNA Genes and Regulates Their Expression

Ribosomal Protein L11 Associates with c-Myc at 5 S rRNA and tRNA Genes and Regulates Their Expression

Ribosomopathies: human disorders of ribosome dysfunction

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

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