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Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4294-4306
By
From the Life Science Division, Lawrence Berkeley National Laboratory
(LBNL), Berkeley, CA; the Département de Pédiatrie et
Laboratoire d'Hématologie, Hôpital Bicêtre,
Assistance Publique-Hôpitaux de Paris, et Faculté de
Médecine Paris Sud, Université Paris XI, Bicêtre,
France; the Unit of Clinical Genetics, Department of Genetics and
Pathology, Uppsala University Children's Hospital, Uppsala, Sweden;
the Departments of Pediatrics and Genetics, University of Torino,
Torino, Italy; the Department of Medical Sciences, University of
Eastern Piedmont, Novara, Italy; the DBA Study Group, Division of
Haematology, Department of Cellular and Molecular Sciences, St.
George's Hospital Medical School, London, UK; the
Universität-Kinderklinik, Freiburg, Germany; the Laboratoire de
Biochimie, Hôpital Necker, Assistance Publique-Hôpitaux de
Paris, Paris, France; and Banque d'ADN, Genethon III, Evry, France.
Mutations of the ribosomal protein S19 (RPS19) gene were recently
identified in 10 patients with Diamond Blackfan anemia (DBA). To
determine the prevalence of mutations in this gene in DBA and to begin
to define the molecular basis for the observed variable clinical
phenotype of this disorder, the genomic sequence of the 6 exons and the
5' untranslated region of the RPS19 gene was directly assessed in
DBA index cases from 172 new families. Mutations affecting the coding
sequence of RPS19 or splice sites were found in 34 cases (19.7%),
whereas mutations in noncoding regions were found in 8 patients
(4.6%). Mutations included nonsense, missense, splice sites, and
frameshift mutations. A hot spot for missense mutations was identified
between codons 52 and 62 of the RPS19 gene in a new sequence consensus
motif
W-[YFW]-[YF]-x-R-[AT]-A-[SA]-x-[AL]-R-[HRK]-[ILV]-Y. No
correlation between the nature of mutations and the different patterns
of clinical expression, including age at presentation, presence of
malformations, and therapeutic outcome, could be documented. Moreover,
RPS19 mutations were also found in some first-degree relatives
presenting only with isolated high erythrocyte adenosine deaminase
activity and/or macrocytosis. The lack of a consistent relationship
between the nature of the mutations and the clinical phenotype implies
that yet unidentified factors modulate the phenotypic expression of the
primary genetic defect in families with RPS19 mutations.
DIAMOND BLACKFAN anemia (DBA), or
congenital pure red blood cell aplasia, is a rare disorder affecting 4 to 7 children per million live births.1-4 It typically
presents in infancy as a regenerative macrocytic anemia and is variably
associated with a wide range of physical abnormalities, predominantly
craniofacial, but also including thumb, cardiac, and urogenital
malformations.2,4-6 Although the anemia is
steroid-responsive in 70% of affected children, this response may not
be sustained and up to 40% of individuals become eventually dependent
on a long-term red blood cell transfusion program.4 In
steroid-responders, a macrocytosis and a mild anemia generally persist
despite response to therapy,2,7 most often in association
with elevated erythrocyte adenosine deaminase (eADA)
activity.8,9 DBA is most commonly sporadic, with a clearly
positive family history in only 10% to 25% of
patients,2,4,5 usually showing an autosomal dominant
pattern of inheritance. However, increased eADA activity may also be
found in some apparently unaffected individuals from DBA
families,8,9 whereas in other cases, a family history may
be inferred from a previously unexplained episode of moderate
macrocytic anemia during childhood or pregnancy.10,11
It has been uncertain whether DBA, which is clearly heterogeneous with
respect to clinical phenotype, represents a single or overlapping group
of disorders. Its pathophysiology is still difficult to define, despite
extensive in vitro characterization of bone marrow or peripheral
erythroid progenitors. Results from in vitro progenitor culture studies
are generally consistent with an intrinsic erythroid cell defect
predominantly affecting differentiation.7,12-15 Preliminary
studies have ruled out a number of potential candidate genes, including
those encoding the erythropoietin receptor,16 stem cell
factor or its receptor,17-19 and
interleukin-9.20 Recently, a balanced translocation,
t(X;19), was identified in a DBA patient,21 allowing a
first locus for DBA to be assigned to chromosome 19q13.2,22 although genetic heterogeneity was shown by the failure of DBA to
cosegregate with this locus in some families.23,24 The
cloning of the chromosome 19q13 translocation breakpoint showed the
translocation to interrupt the gene encoding the ribosomal protein S19
(RPS19). Subsequent analysis identified mutations in the coding
sequence of 1 allelle of RPS19 gene in 10 of 40 unrelated DBA
patients.25 In the present work, we systematically studied
the RPS19 gene in a cohort of 172 DBA families (190 patients) who
fulfilled diagnostic criteria for DBA agreed by the DBA Working Group
of the European Society for Paediatric Haematology and Immunology
(ESPHI).26 We found heterozygosity for mutations affecting
the RPS19 gene in 42 of 172 index patients (24.4%), including many
mutations that had not been previously described. We were unable to
find a mutation in RPS19 gene in the other 76% of families, confirming the genetic heterogeneity of DBA. Mutations in RPS19 gene identified included nonsense, missense, splice site, and frameshift mutations, as
well as complete loss of a presumed normal allele. These different mutations were found scattered along the entire span of the RPS19 gene.
Interestingly, mutations in RPS19 gene were also found in some
apparently unaffected individuals from DBA families, presenting only
with an isolated elevation of eADA.9 We also collected extensive clinical and biological features of 216 DBA patients (172 from the present report and the 44 previously
reported3,22,23,25). RPS19 gene was mutated in 56 of these
216 patients (26%). The presence or absence of different types of
physical anomalies or the various types of long-term therapeutic
responses could not be associated with a specific pattern of mutations.
The lack of a consistent relationship between the nature of the
mutations and the clinical phenotype implies that yet unidentified
factors modulate the phenotypic expression of the primary genetic
defect in families with RPS19 mutations.
Patients
Measurement of eADA Activity
RPS19 Sequence Analysis The genomic DNA sequence for the 6 exons and the 450-bp sequence upstream of the first exon (5'UTR) were determined for each DNA sample. Four polymerase chain reaction (PCR) fragments spanning the 5'UTR and the 6 exons were amplified from 200 ng of genomic DNA in 50 µL reactions using Taq polymerase. The PCR primers25 and additional internal primers were used for fluorescent automated DNA sequencing, performed using Applied Biosystems 373 or 377 DNA sequencer and ABI Big Dye Terminator sequencing kits (Perkin Elmer, Foster City, CA).29 All sequence variations identified were verified on the complementary strand using an independent PCR product. When a particular mutation was detected in a patient, its presence was determined in DNA of all other available family members. To confirm that the observed changes in nucleotide sequence found in DBA patients represented mutations rather than polymorphisms, DNA derived from 50 healthy blood bank donors representing 100 unrelated chromosomes was also sequenced for the 5'UTR and the first 5 exons.Comparative Analysis of RPS19 Sequence The amino acid sequence of human RPS19 was analyzed for various sequence motifs using ScanProsite Protein against PROSITE (ExPASy; HCU, Geneva, Switzerland). Analysis of secondary and tertiary structures of RPS19 was determined using Hierarchical Neural Network and GOR IV (IBCP, Lyon, France).30,31 Alignment of RPS19 amino acid sequence originating from 20 different species was performed using the software package MultAlin (Corpet F; INRA, Toulouse, France; accession no. of sequences in Appendix 1). High consensus value was set at 90%, and the low consensus value was set at 50%. From the set of 20 protein sequences used, a search for blocks was performed with MATCH-BOX_server 1.2 (Molecular Biology, University of Namur, Namur, Belgium).32 Similarly, the search for motifs from the set of sequences was performed using MEME version 2.2 from Baylor College of Medicine (Houston, TX).33Statistical Analysis Descriptive statistics are presented as the percentages and means ± 1 SD. The significance of observed differences was tested using the 2 statistic and, when more appropriate for small
samples, a two-tailed Fisher's exact test. Kruskal-Wallis H
nonparametric test was used for comparison of age at diagnosis and
prevalence of malformations, because variance within groups appeared to
be different. Statistical analysis was performed using Epi-Info 6.04b
(Center for Disease Control, Atlanta, GA).
RPS19 Gene Mutations in 172 DBA Index Cases Using direct sequencing of genomic DNA, we screened for RPS19 mutations in the index cases of 172 families. In 42 of the 172 families studied, 1 of the RPS19 alleles was found to harbor a mutation, defined as a sequence variation not seen in 100 normal chromosomes. Thirty-one of the mutations were in the coding region of the gene, whereas 3 others were at splice sites, 3 were in the first noncoding exon, and 7 were in intronic regions (2 patients each exhibiting 2 mutations). Nonsense mutations generating a premature stop codon were detected in 10 cases (Fig 1). These mutations were restricted to exons 2 to 5, up to codon 94. Missense mutations resulting in an amino acid substitution were noted in 12 cases (Fig 2). Insertions of 1 to 3 nucleotides were found in 2 cases, resulting in a shift of the reading frame in 1 case, with the other presenting with a 3 nucleotides insertion resulting in the addition of a glutamine at codon 19 (Fig 3). Deletions of 1 or 2 nucleotides were found in 6 cases, affecting the reading frame, whereas a larger deletion (31 bp) was found in 1 case (Fig 3). Mutations affecting splice sites were observed in 3 cases.
Polymorphisms Affecting the RPS19 Gene The following variations from published sequence were found in the RPS19 gene of 50 normal individuals: exon 1, in position 550
from the ATG, C in 54% or T in 46% of normal chromosomes; intron 2, starting at position 77 downstream of the end of exon 2, GGT CCC TGG
CAG GCG AGG in 54% and GGT CCT GGC AGG GGA GG in 46%; exon 3, 164C T in 1 chromosome; intron 4, 14 nucleotides downstream of
the end of exon 4, A in 50% or G in 50%.
Association Between Mutations and Conserved Sequence Motifs Distribution of all 42 different mutations along the RPS19 gene reported in the present study as well as the 10 mutations identified in the earlier report25 is summarized in Fig 4. The majority (11/16) of the missense mutations was observed between codons 52 and 62, although this region of the predicted protein did not correspond to any previously identified functional motif. However, the search for amino acid motifs from the alignment of different RPS19 protein sequences showed 3 significant sequence motifs. Motif 1 started at codon 52 in human RPS19, with the multilevel consensus sequence W52-[YFW]-[YF]-[VTILK]-R-[AT]-A-[SA]-[IVLT]-[AL]-R-[HRK]-[ILV]-Y65. Most of the missense mutations (11/16) affected this motif, which was only found in the different RPS19e proteins using various databases. Interestingly, mutations affecting the highly conserved Arg56 and Arg62 residues were seen in 3 and 6 cases, respectively. Motif 2 started at codon 31 of human RPS19 with the following sequence: P31-[EGDQ]-[WY]-[VAIS]-D-[IFTLV]-[VIT]-K-[TLM]-[GAS]-[VAIKMRST]-[HSDFGN]-[KNR]-E-[LMR]-[APRS]-P47. No mutation was identified in this motif. Motif 3 started at codon 120 of human RPS19 with the following sequence: G120-R-[RVKLI]-[ILV]-[TS]-[PKEQS]-[QEKNS]-G-[RQ]-[RKS]-[DF]-L-D-[RK]-[IV]-A135. Two of the missense mutations identified were found within motif 3.
Phenotype of Patients Studied A total of 216 families were available for phenotype-genotype correlations analysis, 76 families from France, 56 from Italy, 37 from the United Kingdom, 29 from Germany, and 18 from Sweden. The cohort of index cases (sex ratio: M/F: 1/1.04) exhibited the expected range of DBA phenotypes (Table 1). Their median age at presentation was 2.0 months (range, 0 to 240 months) and 41.5% had associated physical anomalies. Sixty-two percent had initially responded to steroids. At the time of the genetic study, the mean age was 151 ± 134 months, 45.1% of the patients were transfusion-dependent, 31.4% were steroid-dependent, and 19% were transfusion-independent with no other treatment, whereas 5 patients had received bone marrow transplantation (BMT; 2.5%) and 4 (2%) were dead.
RPS19 Mutations in First-Degree Relatives Sporadic cases. No mutation was found in any of the healthy and hematologically normal family members of the 38 sporadic cases in whom a mutation had been detected (of a total of 154 sporadic index cases studied). Dominant cases. Cosegregation between the observed RPS19 mutation and the DBA phenotype was consistently found in the 8 dominant families in which mutations affecting coding regions or splice sites had been identified in the index case. A patient from 1 additional dominant family (F5) showed a mutation in the noncoding region of RPS19 gene, and this mutation could be documented in only 1 of 3 affected individuals in this family. A mutation occurring in intron 1 in another dominant case (F58) still remains to be explored in other family members, when DNA becomes available. Of the 23 dominant families in which no mutations had been detected, 3 had previously been shown not to be linked with 19q13 and 3 had shown equivocal linkage, whereas cosegregation analysis in the remaining families would have been consistent with 19q13 linkage (data not shown). However, it should be noted that many of the latter group of families often comprises no more than 4 individuals. It remains unclear whether the DBA phenotype thus segregates with markers on 19q13.2 by chance or more complex rearrangements of the chromosome 19q13.2 region are occurring in these DBA patients. Familial high eADA individuals.
RPS19 mutations were found in 11 of 25 index cases with 1 or more
first-degree relatives showing isolated high eADA activity (familial
high eADA) or other hematological abnormalities. In 5 families, the
mutation detected in the proband was found in all family members with
high eADA or macrocytosis. In 4 of these 5 families (F4, E10, F66, and
G24), either a mutation in the coding sequence or a mutation affecting
a splice site cosegregated with either classical DBA or other
hematological abnormalities (Fig 5A and B).
All of these individuals with an RPS19 mutation had an increase of eADA
activity greater than +3 SD of the normal values. In the fifth family
(I11), the same missense mutation was detected in a pair of monozygotic
twins with classical DBA and their father, who had persistent
macrocytosis but a normal eADA. Conversely, in 6 other families in
which a mutation in RPS19 gene was found, there was only partial
cosegregation of the mutation with isolated hematological or
biochemical abnormalities. A missense mutation in 1 transfusion-dependent DBA patient (F7) was not found in any of the 3 brothers who presented with a mild increase in eADA. In family F1, the
4-bp deletion in exon 1 was present in the DBA affected proband as well
in 2 individuals presenting with the isolated high eADA phenotype (Fig
6A). However, this deletion was also found in another family member
despite both normal red blood cell indices and normal eADA activity. A
splice site defect found in the 2 DBA cases of the dominant family E3
was not found in the brother of the proband, whose eADA activity was
between +2 and +3 SD above the normal mean
(Fig 6B).
Phenotype-Genotype Correlations No constant clinical features or therapeutic outcome could be found within patients from different families displaying identical mutations in RPS19 gene. Similarly, the clinical expression or therapeutic response was different in various family members in dominant families, although displaying the same mutations in RPS19 gene. This was also illustrated by the discrepancy between the pair of monozygotic twins from family I11 with respect to physical anomalies (Fig 7). Despite their apparent genotypic identity, only 1 showed duplication of the thumb. The twins were identical for the following markers: D19S197, D19S408 at the DBA locus on 19q13.2; STR at the PAH locus on chromosome 12q; (GGAA)n, repeat microsatellite located548 bp upstream from the ATG start codon of the R-EPO locus on 19s13.2; and D5S658 and RPS on 5q. The twins were
thus considered to be monozygotic. When grouping individuals with
mutations in the coding sequence or affecting splice site of RPS19 gene
according to the location of the mutation, we were unable to correlate
the clinical phenotype with the length of conservation of the native
protein or with the conservation of any of the 3 motifs described
above. Specifically, mutations involving motif 1 were not associated
with a specific phenotype or outcome.
A major advance in the genetics of DBA was recently achieved with the description of a series of mutations affecting the RPS19 gene in 10 unrelated DBA patients.25 In the present study involving a large international collaborative effort, we report the detailed characterization of mutations in RPS19 gene in 194 patients from 172 new families with DBA and attempt to establish the potential relationship between molecular defects and phenotype. Our results significantly extend the initial findings based on a small group of patients and show that alterations in RPS19 gene can be documented in up to 26% of DBA patients.
Sequences used were retrieved from NCBI Entrez Protein query: from mammalian species: human HUMS19RP (337733), rat RS19RAT (133857), pig RS_19PIG (2500494); from Mya arenaria RS19_MYAAR (2500495); from Drosophila melanogaster RS19_DROME (730639); from fungi: Schizosaccharomyces pombe SPBC649 (3136024), Emericella nidulans RS19_EMENI (133844), Saccharomyces cerevisiae S19A (133864), Saccharomyces cerevisiae S19eB (2119095), Saccharomyces pastorianus S16A (4369); from Archaea bacteria: Pyrococcus horikoshii (3257748), Methanobacterium thermoautotrophicum R19E_METTH (3122650), Methanococcus jannaschii R19E_METJA (1591407), Archeoglobus fulgidus rps19E (2648466); from Entamoeba histolytica RS19_ENTHI (3122799); from nematodes: Ascaris suum RS19_ASCSU (730457), Ascaris suum eliminated protein n°1 R19G_ASCSU (133843), Ascaris lumbricoides (84483), Caenorhabditis elegans (3924845); from plants: rice RS19_ORYSA (730456).
Participating clinical investigators from Italy: A. Lippi (Firenze), G. Forni (Genova), F. Locatelli (Pavia), P.G. Mori (Genova), M. Mair (Brunico), S. Varotto (Padova), M. D'Avanzo (Napoli), B. Nobili (Napoli), G. Andria (Napoli), F. Massolo (Modena), G. Russo (Catania), G.P. Bagnara (Bologna), G. Izzi (Parma), G. Castaman (Vicenza), M.R. Govoni (Ferrara), R. Galanello (Cagliari). Participating clinical investigators from France: A. Babin Boilletot (Strasbourg), A. Barruchel (Paris), D. Berets (Clamart), C. Berger (Saint Etienne), F. Bernaudin (Créteil), Y. Bertrand (Lyon), S. Blanche (Paris), J.F. Boccara (Paris), P. Bordigoni (Nancy), C. Chenel (Papeete), B. Chevallier (Boulogne Billancourt), B. Coiffier (Lyon), G. Daltroff (Belfort), M. Debré (Paris), A. Deville (Nice), H. Dombret (Paris), J.P. Dommergues (Le Kremlin-Bicêtre), J. Donadieu (Paris), V. Dorvaux (Metz), F. Dreyfus (Paris), R. Girot (Paris), R. Goddon (Montluçon), J.M. Guillard (Bordeaux), M. Guillot (Lisieux), P. Labrune (Clamart), C. Lajarrige (Laon), J.P. Lamagnere (Tours), A. Lambiliotte (Lille), T. Leblanc (Paris), O. Lejars (Tours), Cl. Lejeune (Colombes), G. Leverger (Paris), L. de Lumley (Limoges), G. Margueritte (Montpellier), F. Méchinaud (Nantes), J.L. Mesnil (Flers), M.J. Milleret Proyart (Sens), M. Monconduit (Rouen), M. Munzer (Reims), C. Narcy (Saint Germain en Laye), R. Ouelbany (Margency), B. Pautard (Amiens), H. Perrimond (Marseille), N. Philippe (Lyon), M.P. Pignol (Mont de Marsan), H. Piguet (Rouen), A. Plou (Nantes), A. Robert (Toulouse), Cl. Roy (Paris), D. Quillerou (Troyes), G. Souillet (Lyon), H. Testard (Saint Denis de la Réunion), C. Saint-Aimé (Fort de France), G. Schaison (Paris), D. Stamm (Lyon), J.L. Stéphan (Saint Priez en Jarrez), Ph. Tron (Rouen), and C. Vervel (Compiègne). Participating clinical investigators from Germany: K. Bode (Bonn), J. Budde (Freiburg), H. Cario (Ulm), W.M. Debatin (Heidelberg), W. Dörffel (Berlin), W. Eberl (Braunschweig), E. Harms (Münster), C. Hasan (Bonn), L. Kanz (Tubingen), E. Kohne (Ulm), S. Müller-Weihrich (München), J. Ritter (Münster), T. Wiesel (Datteln), N. Yudina (Voronezh). Participating clinical investigators from United Kingdom: B. Gibson, E. Simpson (Glasgow), P. Darbyshire, D. Milligan (Birmingham), R. Stevens, A. Will (Manchester), S. Davies (Yeovil), A. Parker (Edinburgh), A. Goringe (Cardiff), M. Barraclough (Hull), S. Kinsey, C. Shiach (Leeds), P. Skacel (London), J. Reiser (Stevenage), J. Martin (Liverpool), J. Wimperis (Norwich), K. Dodd (Derby), D. Walker (Nottingham),MReid (Newcastle), L. Lamont (Chichester), S. Haider (Bury), D. King (Aberdeen), R. Wilkie (Dundee). Participating clinical investigators from Sweden: G. Elinder (Stockholm), J.-I. Henter (Stockholm), M. Donner (Lund). Contributors from other countries: G. Cornu (Bruxelles, Belgium), J. Otten (Bruxelles, Belgium), J. Humbert (Genève, Switzerland), T. Révész (Utrechts, The Netherlands), P. Philippet (Montegnee, Belgium), Nancy Olivieri (Toronto, Ontario, Canada), Elizabeth Smibert (Melbourne, Australia), Silvia Brandalise (Campinas, Brasil). Participating laboratories: J.P. Cartron (Paris), L. Croisille (Le Kremlin-Bicêtre), L. Coulombel (Villejuif), P. Gane (Paris), J.L. Pérignon (Paris), P.H. Roméo (Créteil).
The authors acknowledge the DBA working groups of the European Society for Paediatric Haematology and Immunology (ESPHI) and of the Société d'Hématologie et d'Immunologie Pédiatrique (SHIP) and the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP). We are grateful to Dr Philippe Gascard (LBNL) and Dr Sylvain Choquet for their helpful suggestions. We gratefully acknowledge Dr Jamie Cope (University of California, Berkeley, CA) for his help in alignment of protein sequences and Michael Patterson for his help in the sequencing work.
Submitted May 21, 1999; accepted August 3, 1999.
N. Draptchinskaia, I. Dianzani, and S. Ball contributed equally to this work
Supported by grants from the Children's Cancer Foundation of Sweden, the DBA Foundation Inc, the Swedish Medical Research Council, T. and R. Söderbergs Fund, The Beijer Foundation, the Borgström Foundation, R. McDonalds fund, Lundbergs Foundation and Uppsala University, Association Française contre les Myopathies (AFM), Généthon, and Direction de la Recherche Clinique (AP-HP Paris; CRC 950183), Telethon Italia (Grant No. E619), the Max Reinhardt Charitable Trust, LDRD funds from Lawrence Berkeley National Laboratory, and National Institutes of Health Grants No. DK32094 and DK26263.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
Address reprint requests to Thiébaut-Noël Willig, MD, LBNL-LSD, Mail stop 74-217, 1 Cyclotron Rd, Berkeley, CA 94720; e-mail: tnwillig{at}lbl.gov.
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M. A. Rey, S. P. Duffy, J. K. Brown, J. A. Kennedy, J. E. Dick, Y. Dror, and C. S. Tailor Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis Haematologica, November 1, 2008; 93(11): 1617 - 1626. [Abstract] [Full Text] [PDF]
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M. Angelini, S. Cannata, V. Mercaldo, L. Gibello, C. Santoro, I. Dianzani, and F. Loreni Missense mutations associated with Diamond-Blackfan anemia affect the assembly of ribosomal protein S19 into the ribosome Hum. Mol. Genet., July 15, 2007; 16(14): 1720 - 1727. [Abstract] [Full Text] [PDF]
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J. Flygare and S. Karlsson Diamond-Blackfan anemia: erythropoiesis lost in translation Blood, April 15, 2007; 109(8): 3152 - 3154. [Abstract] [Full Text] [PDF]
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J. Flygare, A. Aspesi, J. C. Bailey, K. Miyake, J. M. Caffrey, S. Karlsson, and S. R. Ellis Human RPS19, the gene mutated in Diamond-Blackfan anemia, encodes a ribosomal protein required for the maturation of 40S ribosomal subunits Blood, February 1, 2007; 109(3): 980 - 986. [Abstract] [Full Text] [PDF]
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V. Choesmel, D. Bacqueville, J. Rouquette, J. Noaillac-Depeyre, S. Fribourg, A. Cretien, T. Leblanc, G. Tchernia, L. Da Costa, and P.-E. Gleizes Impaired ribosome biogenesis in Diamond-Blackfan anemia Blood, February 1, 2007; 109(3): 1275 - 1283. [Abstract] [Full Text] [PDF]
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B. L. Ebert, M. M. Lee, J. L. Pretz, A. Subramanian, R. Mak, T. R. Golub, and C. A. Sieff An RNA interference model of RPS19 deficiency in Diamond-Blackfan anemia recapitulates defective hematopoiesis and rescue by dexamethasone: identification of dexamethasone-responsive genes by microarray Blood, June 15, 2005; 105(12): 4620 - 4626. [Abstract] [Full Text] [PDF]
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J. Flygare, T. Kiefer, K. Miyake, T. Utsugisawa, I. Hamaguchi, L. Da Costa, J. Richter, E. J. Davey, H. Matsson, N. Dahl, et al. Deficiency of ribosomal protein S19 in CD34+ cells generated by siRNA blocks erythroid development and mimics defects seen in Diamond-Blackfan anemia Blood, June 15, 2005; 105(12): 4627 - 4634. [Abstract] [Full Text] [PDF]
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Y. Ohene-Abuakwa, K. A. Orfali, C. Marius, and S. E. Ball Two-phase culture in Diamond Blackfan anemia: localization of erythroid defect Blood, January 15, 2005; 105(2): 838 - 846. [Abstract] [Full Text] [PDF]
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L. Da Costa, G. Tchernia, P. Gascard, A. Lo, J. Meerpohl, C. Niemeyer, J.-A. Chasis, J. Fixler, and N. Mohandas Nucleolar localization of RPS19 protein in normal cells and mislocalization due to mutations in the nucleolar localization signals in 2 Diamond-Blackfan anemia patients: potential insights into pathophysiology Blood, June 15, 2003; 101(12): 5039 - 5045. [Abstract] [Full Text] [PDF]
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L. Da Costa, G. Narla, T.-N. Willig, L. L. Peters, M. Parra, J. Fixler, G. Tchernia, and N. Mohandas Ribosomal protein S19 expression during erythroid differentiation Blood, January 1, 2003; 101(1): 318 - 324. [Abstract] [Full Text] [PDF]
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T. Uechi, N. Maeda, T. Tanaka, and N. Kenmochi Functional second genes generated by retrotransposition of the X-linked ribosomal protein genes Nucleic Acids Res., December 15, 2002; 30(24): 5369 - 5375. [Abstract] [Full Text] [PDF]
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J. L. Abkowitz, G. Schaison, F. Boulad, D. L. Brown, G. R. Buchanan, C. A. Johnson, J. C. Murray, and K. M. Sabo Response of Diamond-Blackfan anemia to metoclopramide: evidence for a role for prolactin in erythropoiesis Blood, September 26, 2002; 100(8): 2687 - 2690. [Abstract] [Full Text] [PDF]
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I. Hamaguchi, A. Ooka, A. Brun, J. Richter, N. Dahl, and S. Karlsson Gene transfer improves erythroid development in ribosomal protein S19-deficient Diamond-Blackfan anemia Blood, September 26, 2002; 100(8): 2724 - 2731. [Abstract] [Full Text] [PDF]
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H. Gazda, J. M. Lipton, T.-N. Willig, S. Ball, C. M. Niemeyer, G. Tchernia, N. Mohandas, M. J. Daly, A. Ploszynska, K. A. Orfali, et al. Evidence for linkage of familial Diamond-Blackfan anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease Blood, April 1, 2001; 97(7): 2145 - 2150. [Abstract] [Full Text] [PDF]
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R. Cmejla, J. Blafkova, T. Stopka, J. Jelinek, K. Petrtylova, and D. Pospisilova Ribosomal proteins S3a, S13, S16, and S24 are not mutated in patients with Diamond-Blackfan anemia Blood, January 15, 2001; 97(2): 579 - 580. [Full Text] [PDF]
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TOP
ABSTRACT
INTRODUCTION
