The Frequency and Characteristics of the Ribosomal Protein L5 (RPL5) and Ribosomal Protein L11 (RPL11) Gene Mutations in Patients with Diamond-Blackfan Anemia in the Czech National Registry

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3103-3103
Author(s):  
Dagmar Pospisilova ◽  
Radek Cmejla ◽  
Jana Cmejlova ◽  
Helena Handrkova ◽  
Jan Stary ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Stop Codon ◽  
Point Mutations ◽  
Ribosomal Subunit ◽  
Premature Stop Codon ◽  
National Registry ◽  
Red Cell ◽  
Large Ribosomal Subunit ◽  
Diamond Blackfan Anemia

Abstract Introduction: Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia that is usually diagnosed during early infancy. Apart from defects in red cell maturation, the disorder is also associated with various physical anomalies in 40% of patients. Mutations in the ribosomal protein (RP) S19 were found in 25% of patients, while mutations in other proteins of a small ribosomal subunit (RPS17 and RPS24) were published only in a small fraction of patients. Recently, mutations in RPL5, RPL11 and RPL35a of a large ribosomal subunit were also disclosed in several DBA patients. Results: The Czech DBA registry currently comprises 31 patients. Mutations in RPL5 were identified in 8/31 patients (26%), and mutations in RPL11 in 2/31 patients (6.5%), implying that mutations in RPL5 account for more Czech DBA cases than mutations in RPS19 (22.6%). As for the classification of mutations, all types were identified, including a nonsense mutation (in RPL11), point mutations (in RPL11 and RPL5), a supposed splicing defect and a small insertion and deletions (all in RPL5). Except for point mutations, all other changes were predicted to cause frameshift with premature stop codon. Since identified alterations were found neither in dbSNP nor in 52 healthy controls, and in two families mutations segregate with the disease, we conclude that they represent true DBA-causative mutations. Although the Czech DBA Registry is rather small, we performed a direct comparison of the group of patients with RPS19 mutations (n=7) with the group of patients with RPL5 mutations (n=8). No differences were found in sex ratio, steroid responsiveness, severity or course of the disease or the treatment outcome. However, patients with RPL5 mutations were generally born small for gestational age (SGA) compared with patients from the RPS19-mutated group. Only one patient (12.5%) with an RPL5 mutation was born with normal birth weight compared to four patients (57.1%) with RPS19 mutations. The second difference was even more striking: all patients with RPL5 mutations had flat thenar and some also an additional thumb anomaly, while no thumb anomalies were observed in patients with RPS19 mutations. It is questionable whether normal RPL5 function is in some way more important for proper thumb development than RPS19. Discussion: The identification of mutations in the genes in DBA patients is also interesting from another point of view. Both proteins RPL5 and RPL11 have been reported to be implicated in the activation of p53 through the interaction with the MDM2 protein, suppressing its E3 ubiquitin ligase function that otherwise directs p53 to a rapid degradation. It is noteworthy that yet another RP of a large ribosomal subunit was described, having exactly the same function – RPL23. Because no RPL23 mutations in our DBA patients were found, the primary function of RPL5 and RPL11 in ribosome biogenesis and/or translation underlies DBA phenotype rather than the conjoint role of RPL5, RPL11 and RPL23 in the p53 regulation. Conclusions: We identified 6 and 2 different mutations in the RPL5 and RPL11 genes, respectively, expanding the repertoire of known DBA-associated mutations. No mutations in the RPL23 were identified, suggesting that aberrant p53 activation due to mutations in RPL5 and RPL11 seems unlikely to be the primary cause of DBA. Patients with RPL5 mutations are more commonly born SGA and have higer frequency of thumb anomalies.

scholarly journals Diamond Blackfan Anemia at the Crossroad between Ribosome Biogenesis and Heme Metabolism

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Deborah Chiabrando ◽  
Emanuela Tolosano
Keyword(s):  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Leukemia Virus ◽  
Ribosomal Subunit ◽  
Pure Red Cell Aplasia ◽  
Feline Leukemia Virus ◽  
Congenital Defects ◽  
Diamond Blackfan Anemia ◽  
Heme Metabolism ◽  
Gene Coding

Diamond-Blackfan anemia (DBA) is a rare, pure red-cell aplasia that presents during infancy. Approximately 40% of cases are associated with other congenital defects, particularly malformations of the upper limb or craniofacial region. Mutations in the gene coding for the ribosomal protein RPS19 have been identified in 25% of patients with DBA, with resulting impairment of 18S rRNA processing and 40S ribosomal subunit formation. Moreover, mutations in other ribosomal protein coding genes account for about 25% of other DBA cases. Recently, the analysis of mice from which the gene coding for the heme exporter Feline Leukemia Virus subgroup C Receptor (FLVCR1) is deleted suggested that this gene may be involved in the pathogenesis of DBA. FLVCR1-null mice show a phenotype resembling that of DBA patients, including erythroid failure and malformations. Interestingly, some DBA patients have disease linkage to chromosome 1q31, where FLVCR1 is mapped. Moreover, it has been reported that cells from DBA patients express alternatively spliced isoforms of FLVCR1 which encode non-functional proteins. Herein, we review the known roles of RPS19 and FLVCR1 in ribosome function and heme metabolism respectively, and discuss how the deficiency of a ribosomal protein or of a heme exporter may result in the same phenotype.

Mutations in Ribosomal Protein Genes of Diamond-Blackfan Anemia Patients in Japan.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3204-3204
Author(s):  
Yuki Konno ◽  
Tsutomu Toki ◽  
Satoru Tandai ◽  
Gang Xu ◽  
Kiminori Terui ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Ribosomal Protein ◽  
Bone Marrow Failure ◽  
Macrocytic Anemia ◽  
Ribosomal Subunit ◽  
Premature Stop Codon ◽  
Reading Frame ◽  
Western Countries ◽  
Diamond Blackfan Anemia ◽  
Increased Risk

Abstract Abstract 3204 Poster Board III-141 Diamond-Blackfan anemia (DBA) is an inherited congenital bone marrow failure syndrome, characterized by red blood cell aplasia, macrocytic anemia, and increased risk of malignancy. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, which occur in about 40% of patients. Approximately 90% of patients present during the first year of life or in early childhood. Recent studies have shown that the disease is associated with heterozygous mutations in the ribosomal protein (RP) genes RPS19, RPS24, and RPS17, encoding small ribosomal subunit proteins, and in RPL5, RPL11 and RPL35a, encoding large ribosomal subunit proteins, in about 50% of patients with DBA in Western countries. There have been no studies to determine the incidence of these mutations in Asian patients with DBA. In this study, 44 probands (46 patients) with DBA in Japan were screened for mutations of the 6 known DBA genes RPS19, RPS24, RPS17, RPL5, RPL11, and RPL35a, in addition to RPS14, which is implicated in the 5q- syndrome, a subtype of myelodysplastic syndrome characterized by a defect in erythroid differentiation. Mutations in RPS19, which have been found in 25% of patients in Western countries, were detected in 6 probands (13.6%). Missense mutations were noted in 5 of these probands, and a frameshift mutation caused by a single-nucleotide insertion was found in 1 case. Three of 7 patients had multiple malformations. Novel mutations in RPL5 were identified in 3 probands (6.8%). Insertion of 2 nucleotides was found in 1 case, affecting the reading frame. Two cases had point mutations, which resulted in a loss of the first initiation codon. All 3 patients with RPL5 mutations had multiple physical anomalies. Remarkably, 2 of 3 patients with RPL5 mutations had cleft palate, whereas no other DBA patients presented with cleft palate. Mutations in RPL11 were identified in 2 patients (4.5%). Deletion of 1 or 2 nucleotides was found in each case, leading to a shift in the reading frame. In contrast to previous reports on patients with RPL11 mutations, thumb anomalies were not seen. Deletion of 1 nucleotide in RPS17 was identified in 1 patient (2.3%), resulting in introduction of a premature stop codon. RPS17 mutations are rare and have been only reported in 2 patients with DBA. Anomalies were not seen in our patient. In summary, RP gene mutations were identified in 27.3% of DBA index cases in Japan. No mutations were detected in RPS14, RPS24 and RPL35a. In Japan, the frequency of mutations in the RP genes appears to be lower than in Western countries. Mutations in RPL5 are associated with multiple physical abnormalities, including cleft palate. Disclosures No relevant conflicts of interest to declare.

Characterization of the Hematologic Phenotype of rpS6 Heterozygous Null Mice as a Model of the Erythroid Failure In Diamond-Blackfan Anemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2033-2033
Author(s):  
Sioban B. Keel ◽  
Janis L. Abkowitz
Keyword(s):  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Conflicts Of Interest ◽  
Macrocytic Anemia ◽  
Ribosomal Subunit ◽  
T Test ◽  
Ribosomal Protein Genes ◽  
Diamond Blackfan Anemia ◽  
Student’S T ◽  
Student’S T Test

Abstract Abstract 2033 Diamond-Blackfan Anemia (DBA) is a congenital form of pure red cell aplasia characterized by a hypoproliferative, macrocytic anemia, congenital anomalies, and a predisposition to cancer. DBA, along with a growing number of human diseases, is linked to defects in ribosome biogenesis. Mutations in at least 10 ribosomal protein genes of both the 40S and 60S ribosomal subunits have now been identified in over 50% of patients with DBA (Narla A, et al. Blood 2010; 115) resulting in ribosomal protein haploinsufficency and in turn a defect in ribosome biogenesis. It remains, however, unknown how these events culminate in erythroid marrow failure. The study of this pathophysiology has been hindered by a lack of animal models. We became aware of the Rps6-deleted mouse as a potential murine model of DBA (Volarevic S, et al. Science 2000; 288). RPS6 is another 40S ribosomal subunit protein required for ribosomal subunit assembly. Haploinsufficiency of RPS6 causes a phenotype reminiscent of DBA during embryogenesis (Panic L, et al. Mol Cell Biol 2006; 26), however, the erythropoietic phenotype of the conditionally-deleted Rps6 heterozygous mouse was unknown. The purpose of these studies is to fully characterize the erythroid phenotype of this mouse as a model of DBA. We demonstrate that deletion of one Rps6 allele in mice results in a macrocytic anemia and leukopenia (an absolute neutropenia and lymphocytopenia, Table 1). Though this finding is not typical, neutropenia has been described in DBA. Like DBA, the anemia is hypoproliferative (corrected reticulocyte counts were equivalent in rpS6 heterozygous and control mice: 3.3% ± 0.21, n= 3 vs. 3.6 ± 0.33, n=3; two-tailed Student's t-test, p= 0.08, which is an inappropriately low value given the deleted animals’ anemia). Flow cytometric analyses of bone marrow and spleen double-stained for Ter119 and transferrin receptor (CD71) demonstrate impaired early erythroid differentiation, evidenced by a relative expansion in the proerythroblast and basophilic erythroblast populations. Hematopoietic colony assays confirm this early defect. These data suggest that haploinsufficiency of rpS6 impacts both erythropoiesis and granulopoiesis, and since the mice are not thrombocytopenic, the effect appears lineage specific, rather than occurring in a common progenitor cell. Polysome profiles to confirm a defect in ribosome biogenesis are pending. Since heterozygous mice recapitulate the erythroid phenotype of DBA, we treated the mice with standard and potential DBA therapies. Specifically, mice received 2 mg/kg/day of prednisone for 12 weeks. There was no improvement in the hemoglobin or MCV in treated animals. As DBA and 5q- syndrome myelodysplastic syndrome (MDS) share an erythroid phenotype and both result from a haploinsufficiency of a ribosomal protein, we also tested whether the macrocytic anemia in rpS6 heterozygous mice responds to lenalidomide (Revlimid®, gift from Celgene Corporation, San Diego, CA). Mice received 3 mg/kg/day of lenalidomide by oral gavage for 12 weeks. The hemoglobin increased in control mice and markedly increased in rpS6 heterozygous mice after 12 weeks of therapy (13.5 ± 0.4 to 14.9 ± 0.2, p= 0.0 and 7.9 g/dL ± 0.9 to 10.3 ± 0.8, p= 0.01, respectively; mean ± SEM, Student's t-test, paired). Additionally, the MCV decreased with therapy in both groups (49.1 fL ± 1.4 to 41.1 ± 0.2, p=0.005 and 57.4 ± 1.1 to 53.77 ± 1.4, p=0.08). With the caveat that we did not monitor drug levels achieved in vivo, these data suggest that lenalidomide improves hemoglobinization and deserves further study in DBA. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism

2019 ◽  
Vol 48 (2) ◽  
pp. 770-787 ◽  
Author(s):  
Marco Lezzerini ◽  
Marianna Penzo ◽  
Marie-Françoise O’Donohue ◽  
Carolina Marques dos Santos Vieira ◽  
Manon Saby ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Bone Marrow Failure ◽  
Missense Variant ◽  
Ribosomal Protein Gene ◽  
Multiple Cancer ◽  
Bone Marrow Failure Syndrome ◽  
Diamond Blackfan Anemia ◽  
Downstream Effects ◽  
Variant Analysis

Abstract Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5′UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5′UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5′UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts.

scholarly journals Therapeutic base and prime editing of COL7A1 mutations in recessive dystrophic epidermolysis bullosa

2021 ◽  
Author(s):  
Sung-ah Hong ◽  
Song-Ee Kim ◽  
A-young Lee ◽  
Gue-ho Hwang ◽  
Jong Hoon Kim ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Ex Vivo ◽  
Stop Codon ◽  
Point Mutations ◽  
Premature Stop Codon ◽  
Loss Of Function ◽  
Dystrophic Epidermolysis Bullosa ◽  
Immunodeficient Mice ◽  
Type Vii Collagen ◽  
Recessive Dystrophic Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by loss-of-function mutations in the COL7A1 gene, which encodes type VII collagen (C7), a protein that functions in skin adherence. From 36 Korean RDEB patients, we identified a total of 69 pathogenic mutations (40 variants without recurrence), including point mutations (72.5%) and insertion/deletion mutations (27.5%). We used base and prime editing to correct mutations in fibroblasts from two patients (Pat1, who carried a c.3631C>T mutation in one allele, and Pat2, who carried a c.2005C>T mutation in one allele). We applied adenine base editors (ABEs) to correct the pathogenic mutation or to bypass a premature stop codon in Pat1-derived primary fibroblasts. To expand the targeting scope, we also utilized prime editors (PEs) to correct the mutations in Pat1- and Pat2-derived fibroblasts. Ultimately, we found that both ABE- and PE-mediated correction of COL7A1 mutations restored full-length C7 expression, reversed the impaired adhesion and proliferation exhibited by the patient-derived fibroblasts, and, following transfer of edited patient-derived fibroblasts into the skin of immunodeficient mice, led to C7 deposition within the dermal-epidermal junction. These results suggest that base and prime editing could be feasible strategies for ex vivo gene editing to treat RDEB.

scholarly journals Chaperone-E3 Ligase Complex HSP70-CHIP Mediates Ubiquitination of Ribosomal Protein S3

2018 ◽  
Vol 19 (9) ◽  
pp. 2723 ◽  
Author(s):  
Inwoo Hwang ◽  
Sung-Woo Cho ◽  
Jee-Yin Ahn
Keyword(s):  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Ribosomal Subunit ◽  
E3 Ligase ◽  
Interacting Protein ◽  
Akt Activation ◽  
Protein Levels ◽  
40S Ribosomal Subunit ◽  
Subsequent Degradation ◽  
Ribosomal Protein S3

In addition to its role in ribosome biogenesis, ribosomal protein S3 (RPS3), a component of the 40S ribosomal subunit, has been suggested to possess several extraribosomal functions, including an apoptotic function. In this study, we demonstrated that in the mouse brain, the protein levels of RPS3 were altered by the degree of nutritional starvation and correlated with neuronal apoptosis. After endurable short-term starvation, the apoptotic function of RPS3 was suppressed by Akt activation and Akt-mediated T70 phosphorylation, whereas after prolonged starvation, the protein levels of RPS3 notably increased, and abundant neuronal death occurred. These events coincided with ubiquitination and subsequent degradation of RPS3, controlled by HSP70 and the cochaperone E3 ligase: carboxy terminus of heat shock protein 70-interacting protein (CHIP). Thus, our study points to an extraribosomal role of RPS3 in balancing neuronal survival or death depending on the degree of starvation through CHIP-mediated polyubiquitination and degradation.

scholarly journals Association of snR190 snoRNA chaperone with early pre-60S particles is regulated by the RNA helicase Dbp7 in yeast

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mariam Jaafar ◽  
Julia Contreras ◽  
Carine Dominique ◽  
Sara Martín-Villanueva ◽  
Régine Capeyrou ◽  
...  
Keyword(s):  
Ribosomal Rna ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Ribosomal Subunit ◽  
Rna Helicase ◽  
Genetic Interactions ◽  
Large Ribosomal Subunit ◽  
Base Pairing ◽  
Peptidyl Transferase ◽  
Peptidyl Transferase Center

AbstractSynthesis of eukaryotic ribosomes involves the assembly and maturation of precursor particles (pre-ribosomal particles) containing ribosomal RNA (rRNA) precursors, ribosomal proteins (RPs) and a plethora of assembly factors (AFs). Formation of the earliest precursors of the 60S ribosomal subunit (pre-60S r-particle) is among the least understood stages of ribosome biogenesis. It involves the Npa1 complex, a protein module suggested to play a key role in the early structuring of the pre-rRNA. Npa1 displays genetic interactions with the DExD-box protein Dbp7 and interacts physically with the snR190 box C/D snoRNA. We show here that snR190 functions as a snoRNA chaperone, which likely cooperates with the Npa1 complex to initiate compaction of the pre-rRNA in early pre-60S r-particles. We further show that Dbp7 regulates the dynamic base-pairing between snR190 and the pre-rRNA within the earliest pre-60S r-particles, thereby participating in structuring the peptidyl transferase center (PTC) of the large ribosomal subunit.

scholarly journals The catalytic activity of the translation termination factor methyltransferase Mtq2-Trm112 complex is required for large ribosomal subunit biogenesis

2020 ◽  
Vol 48 (21) ◽  
pp. 12310-12325
Author(s):  
Caroline Lacoux ◽  
Ludivine Wacheul ◽  
Kritika Saraf ◽  
Nicolas Pythoud ◽  
Emmeline Huvelle ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Ribosome Biogenesis ◽  
Translation Termination ◽  
Ribosomal Subunit ◽  
Efficient Production ◽  
Large Ribosomal Subunit ◽  
Termination Factor ◽  
Domains Of Life ◽  
Quality Control Mechanism ◽  
Translation Termination Factor

Abstract The Mtq2-Trm112 methyltransferase modifies the eukaryotic translation termination factor eRF1 on the glutamine side chain of a universally conserved GGQ motif that is essential for release of newly synthesized peptides. Although this modification is found in the three domains of life, its exact role in eukaryotes remains unknown. As the deletion of MTQ2 leads to severe growth impairment in yeast, we have investigated its role further and tested its putative involvement in ribosome biogenesis. We found that Mtq2 is associated with nuclear 60S subunit precursors, and we demonstrate that its catalytic activity is required for nucleolar release of pre-60S and for efficient production of mature 5.8S and 25S rRNAs. Thus, we identify Mtq2 as a novel ribosome assembly factor important for large ribosomal subunit formation. We propose that Mtq2-Trm112 might modify eRF1 in the nucleus as part of a quality control mechanism aimed at proof-reading the peptidyl transferase center, where it will subsequently bind during translation termination.

Remission in Patients with Diamond Blackfan Anemia (DBA) Appears to Be Unrestricted by Phenotype or Genotype

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3092-3092 ◽  
Author(s):  
Hun Lee ◽  
Charalampos Lyssikatos ◽  
Eva Atsidaftos ◽  
Ellen Muir ◽  
Hanna Gazda ◽  
...  
Keyword(s):  
Median Duration ◽  
Congenital Anomalies ◽  
Ribosome Biogenesis ◽  
Genetic Disorder ◽  
Total Duration ◽  
Genotypic Difference ◽  
Red Cell ◽  
Transfusion Therapy ◽  
Female Ratio ◽  
Diamond Blackfan Anemia

Abstract Background: DBA is a rare genetic disorder characterized by faulty ribosome biogenesis, leading to pro-apoptotic erythropoiesis and red cell failure. The Diamond Blackfan Anemia Registry (DBAR) was established in 1993 to provide a robust database for investigating the biology and epidemiology of DBA. The DBAR defines remission in DBA as independence from red cell transfusion or corticosteroid therapy for greater than 6 months. An understanding of factors influencing DBA remission may provide insights into the pathophysiology of DBA and ultimately can lead to improved treatment options. Method: Patients were enrolled in the DBAR with informed consent. Patients who met the remission criteria for this study were evaluated. Patients who reported a remission were contacted and completed a “remission questionnaire”; further information was obtained from the patients’ physicians and verified, where possible, from medical records. Results: Of 555 patients enrolled in the DBAR, 67 patients have experienced a remission (actuarial likelihood approximately 20%). The male: female ratio for remission patients vs. the total DBAR population is 1:0.97 vs. 1:1.03, respectively. Sixty-four percent of patients have congenital anomalies, compared to 47% in the total population; the difference is not statistically significant. All categories of congenital anomalies (e.g. orofacial, cardiac, renal, skeletal, etc.) are represented in the remission population. The median age at diagnosis is 2.9 months (range, 0 to 14.9 years). The majority of patients were started on 2mg/kg/day of prednisone or methylprednisolone at a median age of 3.6 months (range, 4 days to 15.2 years). Sixty-six percent entered remission while on steroid therapy. The median total duration on steroids was 36 months (range, 1 month to 37.6 years) and the median duration from start of steroids to beginning of taper was 3.6 months (range, 1 month to 4.6 years). Seventeen percent of patients went into remission with less than one year of steroids and 55% were in remission within 5 years of start of steroids. Fifteen percent remitted while receiving chronic transfusion therapy. Six percent never received steroids prior to remission and 7.5% of remitters initially responded to steroids but became steroid refractory prior to remission. Median duration of treatment to remission and duration of remission were 16 months (range, 6 months to 38.2 years) and 14 years (range, 1 to 46.8 years) respectively. The median age of remission was 6.4 years (range, 0.8 to 39 years); males 6.5 years (range, 0.8 to 39 years) and females 6.3 years (range, 1.1 to 26 years). Of note, remissions were observed in DBA patients or in affected family members of probands with mutations in 4 of the 6 genes (RPS 19, RPS 24, RPL35a, and RPS11) known to be mutated in DBA as well as in those with no known mutation, suggesting that remission is not restricted to a particular genotype. Additional patients are being genotyped. Conclusion: Remission in patients with DBA is not an uncommon event. Steroid responsiveness is not a prerequisite for remission. There is no obvious phenotypic or genotypic difference between remission and non-remission patients. The expression of a remission phenotype within multiplex families is quite variable. We conclude that remission is not restricted to a particular phenotype or genotype and that the likelihood of remission is influenced by unknown modifier genes and/or epigenetic factors.

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