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1.
Blood ; 136(11): 1262-1273, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32702755

RESUMO

Diamond-Blackfan anemia (DBA) was the first ribosomopathy described and is a constitutional inherited bone marrow failure syndrome. Erythroblastopenia is the major characteristic of the disease, which is a model for ribosomal diseases, related to a heterozygous allelic variation in 1 of the 20 ribosomal protein genes of either the small or large ribosomal subunit. The salient feature of classical DBA is a defect in ribosomal RNA maturation that generates nucleolar stress, leading to stabilization of p53 and activation of its targets, resulting in cell-cycle arrest and apoptosis. Although activation of p53 may not explain all aspects of DBA erythroid tropism, involvement of GATA1/HSP70 and globin/heme imbalance, with an excess of the toxic free heme leading to reactive oxygen species production, account for defective erythropoiesis in DBA. Despite significant progress in defining the molecular basis of DBA and increased understanding of the mechanistic basis for DBA pathophysiology, progress in developing new therapeutic options has been limited. However, recent advances in gene therapy, better outcomes with stem cell transplantation, and discoveries of putative new drugs through systematic drug screening using large chemical libraries provide hope for improvement.

2.
Blood Adv ; 4(8): 1760-1769, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32343795

RESUMO

Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia associated with congenital abnormalities and cancer predisposition. Allogeneic hematopoietic stem cell transplantation (HSCT) can correct the hematological phenotype and is indicated in transfusion-dependent patients. In 70 children reported to the German DBA and French HSCT registries, HSCT was performed from 1985 to 2017. Median age at HSCT was 5.5 years (range, 0.9-17.3 years). Two-thirds of patients (64%) were transplanted from a matched sibling donor (MSD), and most procedures were performed after the year 1999 (73%). Primary engraftment was achieved in all patients. One patient developed secondary graft failure. Cumulative incidence of acute graft-versus-host disease (GVHD) was 24% for °II-IV (95% confidence interval [CI], 16% to 37%) and 7% for °III-IV (95% CI, 3% to 17%); cumulative incidence of chronic GVHD was 11% (95% CI, 5% to 22%). The probability of chronic GVHD-free survival (cGFS) was 87% (95% CI, 79% to 95%) and significantly improved over time (<2000: 68% [95% CI, 47% to 89%] vs ≥2000: 94% [95% CI, 87% to 100%], P < .01). cGFS was comparable following HSCT from a MSD and an unrelated donor (UD). Of note, no severe chronic GVHD or deaths were reported following MSD-HSCT after 1999. The difference of cGFS in children transplanted <10 years of age compared with older patients did not reach statistical significance (<10 years: 90% [95% CI, 81% to 99%] vs 10-18 years 78% [95% CI, 58% to 98%]). In summary, these data indicate that HSCT is efficient and safe in young DBA patients and should be considered if a MSD or matched UD is available. HSCT for transfusion dependency only must be critically discussed in older patients.

3.
Haematologica ; 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32241839

RESUMO

Diamond Blackfan anemia (DBA) is predominantly an autosomal dominant inherited red cell aplasia primarily caused by pathogenic germline variants in ribosomal protein genes. DBA due to pathogenic RPL35A variants has been associated with large 3q29 deletions and phenotypes not common in DBA. We conducted a multi-institutional genotype-phenotype study of 45 patients with DBA associated with pathogenic RPL35A germline variants and curated the variant data on 21 additional cases from the literature. Genotype-phenotype analyses were conducted comparing patients with large deletions versus all other pathogenic variants in RPL35A. Twenty-two of the 45 cases had large deletions in RPL35A. After adjusting for multiple tests, a statistically significant association was observed between patients with a large deletion and steroid-resistant anemia, neutropenia, craniofacial abnormalities, chronic gastrointestinal problems, and intellectual disabilities (p<0.01) compared with all other pathogenic variants. Non-large deletion pathogenic variants were spread across RPL35A with no apparent hot spot and 56% of the individual family variants were observed more than once. In this, the largest known study of DBA patients with pathogenic RPL35A variants, we determined that patients with large deletions have a more severe phenotype that is clinically different from those with non-large deletion variants. Genes of interest also deleted in the 3q29 region that could be associated with some of these phenotypic features include LMLN and IQCG. Management of DBA due to large RPL35A deletions may be challenging due to complex problems and require comprehensive assessments by multiple specialists including immunologic, gastrointestinal, and developmental evaluations to provide optimal multidisciplinary care.

4.
J Clin Invest ; 130(4): 2097-2110, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961825

RESUMO

Despite the effective clinical use of steroids for the treatment of Diamond Blackfan anemia (DBA), the mechanisms through which glucocorticoids regulate human erythropoiesis remain poorly understood. We report that the sensitivity of erythroid differentiation to dexamethasone is dependent on the developmental origin of human CD34+ progenitor cells, specifically increasing the expansion of CD34+ progenitors from peripheral blood (PB) but not cord blood (CB). Dexamethasone treatment of erythroid-differentiated PB, but not CB, CD34+ progenitors resulted in the expansion of a newly defined CD34+CD36+CD71hiCD105med immature colony-forming unit-erythroid (CFU-E) population. Furthermore, proteomics analyses revealed the induction of distinct proteins in dexamethasone-treated PB and CB erythroid progenitors. Dexamethasone treatment of PB progenitors resulted in the specific upregulation of p57Kip2, a Cip/Kip cyclin-dependent kinase inhibitor, and we identified this induction as critical; shRNA-mediated downregulation of p57Kip2, but not the related p27Kip1, significantly attenuated the impact of dexamethasone on erythroid differentiation and inhibited the expansion of the immature CFU-E subset. Notably, in the context of DBA, we found that steroid resistance was associated with dysregulated p57Kip2 expression. Altogether, these data identify a unique glucocorticoid-responsive human erythroid progenitor and provide new insights into glucocorticoid-based therapeutic strategies for the treatment of patients with DBA.

5.
Nucleic Acids Res ; 48(2): 770-787, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31799629

RESUMO

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.


Assuntos
Anemia de Diamond-Blackfan/genética , Processamento Pós-Transcricional do RNA/genética , Proteínas Ribossômicas/genética , Ribossomos/genética , Regiões 5' não Traduzidas/genética , Adolescente , Adulto , Anemia de Diamond-Blackfan/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Criança , Células Eritroides , Feminino , Humanos , Masculino , Mutação/genética , Precursores de RNA/genética , RNA Mensageiro/genética , Sequenciamento Completo do Exoma
6.
Fetal Diagn Ther ; 47(2): 156-164, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31505487

RESUMO

BACKGROUND: Rare causes of fetal anemia requiring intrauterine transfusion (IUT) are challenging for fetal medicine specialists. OBJECTIVES: The aim of this study was to describe the perinatal patterns and prognosis in a consecutive series of fetuses transfused for fetal anemia of rare or unknown etiology, and to propose a protocol of investigation for fetal anemia of undetermined cause and for the management of subsequent pregnancies. METHOD: We conducted a retrospective descriptive study on fetuses transfused for severe anemia of rare or unknown etiology managed in our national referral center (Centre National de Référence d'Hémobiologie Périnatale) and born between 2010 and 2017. RESULTS: During the study period, 584 IUT were performed in 253 fetuses. Among those IUT, 23 (3.9%) were performed for a rare or unknown cause of anemia in 13 fetuses (5.1% of transfused fetuses). The median gestational age at diagnosis was 26 weeks of gestation (WG; range 21-33). Hemoglobin levels ranged from 1.6 to 9.1 g/dL (0.18-0.83 multiples of median) before the first IUT. The fetuses received between 1 and 6 IUT (39% received at least 2 IUT). The definitive etiologies for central anemia were: congenital syphilis, neonatal poikilocytosis, type II congenital dyserythropoietic anemia (CDA), and neonatal hemochromatosis. There was 1 case with suspected type I CDA and 1 with suspected Diamond-Blackfan anemia. There was 1 case of peripheral anemia, secondary to cerebral hemorrhages of different ages, related to a variant of the COL4A1 gene. In 6 fetuses corresponding to 4 mothers, no precise diagnosis was found despite a complete workup. In our series, there were 8 live births, 4 terminations of pregnancy, and 1 intrauterine fetal death. CONCLUSIONS: Fetal anemia of rare or unknown diagnosis represents 5% of all transfused fetuses in our cohort. Fetal and neonatal anemias can be recurrent in further pregnancies, with variable expressivity.

7.
Am J Hum Genet ; 105(5): 1040-1047, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31630789

RESUMO

Variants in genes encoding ribosomal proteins have thus far been associated with Diamond-Blackfan anemia, a rare inherited bone marrow failure, and isolated congenital asplenia. Here, we report one de novo missense variant and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13 (also called eL13), in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477+1G>T, c.477+1G>A, and c.477+2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion. In contrast to observations from Diamond-Blackfan anemia, we detected no evidence of significant pre-rRNA processing disturbance in cells derived from two affected individuals. Consistently, we showed that the insertion-containing protein is stably expressed and incorporated into 60S subunits similar to the wild-type protein. Erythroid proliferation in culture and ribosome profile on sucrose gradient are modified, suggesting a change in translation dynamics. We also provide evidence that RPL13 is present at high levels in chondrocytes and osteoblasts in mouse growth plates. Taken together, we show that the identified RPL13 variants cause a human ribosomopathy defined by a rare skeletal dysplasia, and we highlight the role of this ribosomal protein in bone development.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Nanismo/genética , Mutação de Sentido Incorreto/genética , Proteínas de Neoplasias/genética , Proteínas Ribossômicas/genética , Anemia de Diamond-Blackfan/genética , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
8.
Sci Rep ; 9(1): 6771, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043643

RESUMO

Osmotic gradient ektacytometry is the gold standard to assess red blood cell (RBC) deformability. It has been proposed that, when measured in isotonic condition, RBC deformability at low shear stress would depend on membrane elasticity while it would be influenced by internal viscosity when measured at high shear stress, but this hypothesis needs to be further addressed. Healthy RBCs were rigidified by treatment with lysolecithine (LPC), diamide or nystatine associated with hyperosmolar solutions (OSMO), which reduces membrane surface area, decreases membrane elasticity or promotes cell dehydration, respectively. Diamide treatment resulted in a decrease in isotonic RBC deformability at all shear stresses tested (i.e. from 0.3 to 30 Pa). LPC and OSMO treatments caused a decrease in isotonic RBC deformability above 3 Pa only. Isotonic RBC deformability from patients with hereditary spherocytosis or sickle cell disease was mainly decreased above 1.69 Pa. Our findings indicate that decreased isotonic RBC deformability at shear stresses above 3 Pa would be related to a reduction in the surface-area-to-volume ratio and/or to a loss of membrane elasticity and/or to an increase in internal viscosity while a decrease of RBC deformability below 3 Pa would reflect a loss of membrane elasticity.

9.
Am J Hematol ; 94(6): 667-677, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30916803

RESUMO

MYH9-related disease (MYH9-RD) is a rare, autosomal dominant disorder caused by mutations in MYH9, the gene encoding the actin-activated motor protein non-muscle myosin IIA (NMIIA). MYH9-RD patients suffer from bleeding syndromes, progressive kidney disease, deafness, and/or cataracts, but the impact of MYH9 mutations on other NMIIA-expressing tissues remains unknown. In human red blood cells (RBCs), NMIIA assembles into bipolar filaments and binds to actin filaments (F-actin) in the spectrin-F-actin membrane skeleton to control RBC biconcave disk shape and deformability. Here, we tested the effects of MYH9 mutations in different NMIIA domains (motor, coiled-coil rod, or non-helical tail) on RBC NMIIA function. We found that MYH9-RD does not cause clinically significant anemia and that patient RBCs have normal osmotic deformability as well as normal membrane skeleton composition and micron-scale distribution. However, analysis of complete blood count data and peripheral blood smears revealed reduced hemoglobin content and elongated shapes, respectively, of MYH9-RD RBCs. Patients with mutations in the NMIIA motor domain had the highest numbers of elongated RBCs. Patients with mutations in the motor domain also had elevated association of NMIIA with F-actin at the RBC membrane. Our findings support a central role for motor domain activity in NMIIA regulation of RBC shape and define a new sub-clinical phenotype of MYH9-RD.


Assuntos
Actinas , Membrana Eritrocítica , Eritrócitos Anormais , Perda Auditiva Neurossensorial , Mutação , Cadeias Pesadas de Miosina , Trombocitopenia/congênito , Actinas/genética , Actinas/metabolismo , Membrana Eritrocítica/genética , Membrana Eritrocítica/metabolismo , Membrana Eritrocítica/patologia , Eritrócitos Anormais/metabolismo , Eritrócitos Anormais/patologia , Feminino , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Trombocitopenia/genética , Trombocitopenia/metabolismo , Trombocitopenia/patologia
10.
Blood ; 133(12): 1358-1370, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30700418

RESUMO

Diamond-Blackfan anemia (DBA) is a congenital erythroblastopenia that is characterized by a blockade in erythroid differentiation related to impaired ribosome biogenesis. DBA phenotype and genotype are highly heterogeneous. We have previously identified 2 in vitro erythroid cell growth phenotypes for primary CD34+ cells from DBA patients and following short hairpin RNA knockdown of RPS19, RPL5, and RPL11 expression in normal human CD34+ cells. The haploinsufficient RPS19 in vitro phenotype is less severe than that of 2 other ribosomal protein (RP) mutant genes. We further documented that proteasomal degradation of HSP70, the chaperone of GATA1, is a major contributor to the defect in erythroid proliferation, delayed erythroid differentiation, increased apoptosis, and decreased globin expression, which are all features of the RPL5 or RPL11 DBA phenotype. In the present study, we explored the hypothesis that an imbalance between globin and heme synthesis may be involved in pure red cell aplasia of DBA. We identified disequilibrium between the globin chain and the heme synthesis in erythroid cells of DBA patients. This imbalance led to accumulation of excess free heme and increased reactive oxygen species production that was more pronounced in cells of the RPL5 or RPL11 phenotype. Strikingly, rescue experiments with wild-type HSP70 restored GATA1 expression levels, increased globin synthesis thereby reducing free heme excess and resulting in decreased apoptosis of DBA erythroid cells. These results demonstrate the involvement of heme in DBA pathophysiology and a major role of HSP70 in the control of balanced heme/globin synthesis.


Assuntos
Anemia de Diamond-Blackfan/patologia , Diferenciação Celular , Células Eritroides/patologia , Fator de Transcrição GATA1/metabolismo , Globinas/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Heme/metabolismo , Anemia de Diamond-Blackfan/metabolismo , Proliferação de Células , Células Cultivadas , Células Eritroides/metabolismo , Feminino , Seguimentos , Haploinsuficiência , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Fenótipo , Prognóstico , RNA Interferente Pequeno , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo
12.
Am J Hum Genet ; 103(6): 930-947, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30503522

RESUMO

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain >5% of DBA-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders.


Assuntos
Anemia de Diamond-Blackfan/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Exoma/genética , Éxons/genética , Feminino , Deleção de Genes , Estudos de Associação Genética/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Mutação/genética , Fenótipo , Proteínas Ribossômicas/genética , Ribossomos/genética , Análise de Sequência de RNA/métodos , Sequenciamento Completo do Exoma/métodos
13.
F1000Res ; 72018.
Artigo em Inglês | MEDLINE | ID: mdl-30228860

RESUMO

Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia characterized by a block in erythropoiesis at the progenitor stage, although the exact stage at which this occurs remains to be fully defined. DBA presents primarily during infancy with macrocytic anemia and reticulocytopenia with 50% of cases associated with a variety of congenital malformations. DBA is most frequently due to a sporadic mutation (55%) in genes encoding several different ribosomal proteins, although there are many cases where there is a family history of the disease with varying phenotypes. The erythroid tropism of the disease is still a matter of debate for a disease related to a defect in global ribosome biogenesis. Assessment of biological features in conjunction with genetic testing has increased the accuracy of the diagnosis of DBA. However, in certain cases, it continues to be difficult to firmly establish a diagnosis. This review will focus on the diagnosis of DBA along with a description of new advances in our understanding of the pathophysiology and treatment recommendations for DBA.


Assuntos
Anormalidades Múltiplas , Anemia de Diamond-Blackfan/diagnóstico , Anemia de Diamond-Blackfan/terapia , Humanos
14.
Mol Ther ; 26(10): 2523-2532, 2018 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-30077612

RESUMO

Macrophage migration inhibitory factor (MIF) is elevated in patients with acute kidney injury (AKI) and is suggested as a potential predictor for renal replacement therapy in AKI. In this study, we found that MIF also plays a pathogenic role and is a therapeutic target for AKI. In a cisplatin-induced AKI mouse model, elevated plasma MIF correlated with increased serum creatinine and the severity of renal inflammation and tubular necrosis, whereas deletion of MIF protected the kidney from cisplatin-induced AKI by largely improving renal functional and histological injury, and suppressing renal inflammation including upregulation of cytokines such as interleukin (IL)-1ß, tumor necrosis factor-alpha (TNF-α), IL-6, inducible nitric oxide synthase (iNOS), MCP-1, IL-8, and infiltration of macrophages, neutrophils, and T cells. We next developed a novel therapeutic strategy for AKI by blocking the endogenous MIF with an MIF inhibitor, ribosomal protein S19 (RPS19). Similar to the MIF-knockout mice, treatment with RPS19, but not the mutant RPS19, suppressed cisplatin-induced AKI. Mechanistically, we found that both genetic knockout and pharmacological inhibition of MIF protected against AKI by inactivating the CD74-nuclear factor κB (NF-κB) signaling. In conclusion, MIF is pathogenic in cisplatin-induced AKI. Targeting MIF with an MIF inhibitor RPS19 could be a promising therapeutic potential for AKI.


Assuntos
Lesão Renal Aguda/terapia , Inflamação/terapia , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Proteínas Ribossômicas/administração & dosagem , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Animais , Antígenos de Diferenciação de Linfócitos B/genética , Apoptose/efeitos dos fármacos , Cisplatino/efeitos adversos , Terapia Genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/patologia , Oxirredutases Intramoleculares/antagonistas & inibidores , Rim/efeitos dos fármacos , Rim/patologia , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Camundongos , Camundongos Knockout , NF-kappa B/genética , Necrose , Proteínas Ribossômicas/genética , Transdução de Sinais/efeitos dos fármacos
16.
Eur J Haematol ; 101(4): 566-569, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29969830

RESUMO

Severe iron overload is frequent in dehydrated hereditary stomatocytosis (DHSt) despite well-compensated hemolysis and no or little transfusion requirement. We investigated 4 patients with proven DHSt, in whom the degree of hemolysis was closely related to iron status. Genetic modifiers increasing iron stores (HFE:pCys282Tyr, HAMP:c-153C>T mutations) were accompanied with high liver iron concentrations and increased hemolysis, whereas therapeutic phlebotomies alleviated the hemolytic phenotype. There were no manifestations of hemolysis in one patient with low iron stores. Hemolysis reappeared when iron supplementation was given. The search for genetic or acquired modifiers of iron status and the modulation of iron stores may help in the management of these patients.


Assuntos
Anemia Hemolítica Congênita/diagnóstico , Anemia Hemolítica Congênita/metabolismo , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/metabolismo , Ferro/metabolismo , Fenótipo , Adulto , Alelos , Anemia Hemolítica Congênita/sangue , Anemia Hemolítica Congênita/genética , Biomarcadores , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Proteína da Hemocromatose/genética , Humanos , Hidropisia Fetal/sangue , Hidropisia Fetal/genética , Masculino , Pessoa de Meia-Idade , Mutação , Radiografia
17.
Prenat Diagn ; 38(10): 772-778, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29949202

RESUMO

We report a multiplex family with a GATA1 gene mutation responsible for a massive fetal cerebral hemorrhage occurring at 36 weeks. Two other stillbirth cousins presented with fetal hydrops and congenital hemochromatosis' phenotype at 37 and 12 weeks of gestation. Molecular screening revealed the presence of a c.613G>A pathogenic allelic variation in exon 4 of GATA1 gene in the 3 male siblings and their carrier mothers. The diagnosis of a GATA1 gene mutation may be suspected in cases of male fetuses with intracerebral bleeding, particularly if a history of prior fetal loss(es) and mild maternal thrombocytopenia are also present.


Assuntos
Hemorragia Cerebral/genética , Doenças Fetais/genética , Fator de Transcrição GATA1/genética , Adulto , Feminino , Genes Ligados ao Cromossomo X , Humanos , Mutação , Gravidez
18.
Haematologica ; 103(6): 949-958, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29599205

RESUMO

Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure disorder linked predominantly to ribosomal protein gene mutations. Here the European DBA consortium reports novel mutations identified in the RPL15 gene in 6 unrelated individuals diagnosed with DBA. Although point mutations have not been previously reported for RPL15, we identified 4 individuals with truncating mutations p.Tyr81* (in 3 of 4) and p.Gln29*, and 2 with missense variants p.Leu10Pro and p.Lys153Thr. Notably, 75% (3 of 4) of truncating mutation carriers manifested with severe hydrops fetalis and required intrauterine transfusions. Even more remarkable is the observation that the 3 carriers of p.Tyr81* mutation became treatment-independent between four and 16 months of life and maintained normal blood counts until their last follow up. Genetic reversion at the DNA level as a potential mechanism of remission was not observed in our patients. In vitro studies revealed that cells carrying RPL15 mutations have pre-rRNA processing defects, reduced 60S ribosomal subunit formation, and severe proliferation defects. Red cell culture assays of RPL15-mutated primary erythroblast cells also showed a severe reduction in cell proliferation, delayed erythroid differentiation, elevated TP53 activity, and increased apoptosis. This study identifies a novel subgroup of DBA with mutations in the RPL15 gene with an unexpected high rate of hydrops fetalis and spontaneous, long-lasting remission.


Assuntos
Anemia de Diamond-Blackfan/complicações , Anemia de Diamond-Blackfan/genética , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/etiologia , Mutação , Complicações Hematológicas na Gravidez , Proteínas Ribossômicas/genética , Anemia de Diamond-Blackfan/diagnóstico , Anemia de Diamond-Blackfan/terapia , Apoptose/genética , Biomarcadores , Diferenciação Celular/genética , Linhagem Celular , Proliferação de Células , Análise Mutacional de DNA , Índices de Eritrócitos , Feminino , Genes p53 , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Gravidez , Biossíntese de Proteínas
19.
Eur J Med Genet ; 61(11): 664-673, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29081386

RESUMO

Diamond-Blackfan anemia (DBA) is a rare congenital erythroblastopenia and inherited bone marrow failure syndrome that affects approximately seven individuals in every million live births. In addition to anemia, about 50% of all DBA patients suffer from various physical malformations of the face, hands, heart, or urogenital region. The disorder is almost exclusively driven by haploinsufficient mutations in one of several ribosomal protein (RP) genes, although for ∼30% of diagnosed patients no mutation is found in any of the known DBA-linked genes. Because DBA is such a rare disease with a particularly wide range of clinical phenotypes and molecular signatures, the development of collaborative efforts such as the ERARE-funded European DBA consortium (EuroDBA) has become imperative for DBA research. EuroDBA was founded in 2012 and brings together dedicated clinical and biological researchers of DBA from France, Italy, the Netherlands, Germany, Israel, Poland, and Turkey to achieve a number of goals including the consolidation of data in patient registries, establishment of minimal diagnostic criteria, and projects aimed at more fully describing the different mutations linked to DBA. This review will cover the history of the EuroDBA registries, the methods used by EuroDBA in the diagnosis of DBA, and how the consortium has successfully worked together towards the discovery of new DBA-linked genes and the better understanding their pathophysiological effects.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anemia de Diamond-Blackfan/diagnóstico , Anemia de Diamond-Blackfan/genética , Anormalidades Múltiplas/fisiopatologia , Anemia de Diamond-Blackfan/fisiopatologia , Células da Medula Óssea/patologia , Humanos , Mutação , Proteínas Ribossômicas/genética
20.
Ann Neurol ; 82(1): 133-138, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28556183

RESUMO

Glucose transporter type 1 (GLUT1) deficiency syndrome (GLUT1-DS) leads to a wide range of neurological symptoms. Ketogenic diets are very efficient to control epilepsy and movement disorders. We tested a novel simple and rapid blood test in 30 patients with GLUT1-DS with predominant movement disorders, 18 patients with movement disorders attributed to other genetic defects, and 346 healthy controls. We detected significantly reduced GLUT1 expression only on red blood cells from patients with GLUT1-DS (23 patients; 78%), including patients with inconclusive genetic analysis. This test opens perspectives for the screening of GLUT1-DS in children and adults with cognitive impairment, movement disorder, or epilepsy. Ann Neurol 2017;82:133-138.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Transportador de Glucose Tipo 1/biossíntese , Testes Hematológicos , Proteínas de Transporte de Monossacarídeos/deficiência , Adolescente , Adulto , Erros Inatos do Metabolismo dos Carboidratos/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Transporte de Monossacarídeos/sangue , Transtornos dos Movimentos/sangue , Transtornos dos Movimentos/diagnóstico , Adulto Jovem
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