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1.
BMC Neurol ; 20(1): 352, 2020 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-32950057

RESUMO

BACKGROUND: Moyamoya-like vasculopathy (MMV) and myosin heavy chain 9-related platelet disorders (MYH9-RPDs) or macrothrombocitopenias are rare syndromes. Their association is even more infrequent. CASE PRESENTATION: A 29-year-old female with history of MYH9-RPD, presented to our department for episodes suggesting transient ischemic attacks. Based on the imaging studies that revealed multiple ischemic lesions and stenoses of both distal internal carotid arteries and the arteries of the circle of Willis, the diagnosis of MMV was established. The treatment with Verapamil was initiated, leading to symptom remission. Two months later, the patient presented one episode of dysarthria, followed by involuntary movements of the right upper limb, few days later. Long-term electroencephalogram monitoring depicted epileptiform abnormalities. Resolution of symptoms was obtained after increasing the dose of Verapamil, and initiating Levetiracetam. CONCLUSIONS: This is an interesting case of a patient with two rare pathologies, who presented with cerebral ischemic strokes. To our knowledge there are few cases described in the literature presenting with cerebral hemorrhagic events but none of them with multiple cerebral ischemic lesions. As these cases are very rare, it is important to gather evidence regarding the best approach and treatment strategy.


Assuntos
Ataque Isquêmico Transitório/etiologia , Doença de Moyamoya/complicações , Cadeias Pesadas de Miosina/genética , Trombocitopenia/complicações , Trombocitopenia/genética , Adulto , Feminino , Humanos
2.
J Allergy Clin Immunol ; 146(5): 1194-1200.e1, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32853638

RESUMO

BACKGROUND: We studied 2 unrelated patients with immune thrombocytopenia and autoimmune hemolytic anemia in the setting of acute infections. One patient developed multisystem inflammatory syndrome in children in the setting of a severe acute respiratory syndrome coronavirus 2 infection. OBJECTIVES: We sought to identify the mechanisms underlying the development of infection-driven autoimmune cytopenias. METHODS: Whole-exome sequencing was performed on both patients, and the impact of the identified variants was validated by functional assays using the patients' PBMCs. RESULTS: Each patient was found to have a unique heterozygous truncation variant in suppressor of cytokine signaling 1 (SOCS1). SOCS1 is an essential negative regulator of type I and type II IFN signaling. The patients' PBMCs showed increased levels of signal transducer and activator of transcription 1 phosphorylation and a transcriptional signature characterized by increased expression of type I and type II IFN-stimulated genes and proapoptotic genes. The enhanced IFN signature exhibited by the patients' unstimulated PBMCs parallels the hyperinflammatory state associated with multisystem inflammatory syndrome in children, suggesting the contributions of SOCS1 in regulating the inflammatory response characteristic of multisystem inflammatory syndrome in children. CONCLUSIONS: Heterozygous loss-of-function SOCS1 mutations are associated with enhanced IFN signaling and increased immune cell activation, thereby predisposing to infection-associated autoimmune cytopenias.


Assuntos
Anemia Hemolítica Autoimune/imunologia , Anemia Hemolítica Autoimune/virologia , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/virologia , Trombocitopenia/imunologia , Trombocitopenia/virologia , Adolescente , Anemia Hemolítica Autoimune/genética , Betacoronavirus , Pré-Escolar , Infecções por Coronavirus/imunologia , Haploinsuficiência , Humanos , Masculino , Mutação , Pandemias , Pneumonia Viral/imunologia , Proteína 1 Supressora da Sinalização de Citocina/genética , Trombocitopenia/genética
3.
Int J Hematol ; 112(6): 878-882, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32712863

RESUMO

A 66-year-old woman had experienced abnormal bleeding since the age of 7. Thrombocytopenia was not detected until she was 48, and immune thrombocytopenia was diagnosed at age 66. She also reported experiencing hearing disturbance since the age of 30 and acute renal failure since the age of 61 but reported no visual disturbance. Her younger son, who was 40 years old, also experienced abnormal bleeding since the age of 6, but immune thrombocytopenia was diagnosed as late as age 35. He had no other associated disorders. Laboratory examinations of both mother and son revealed a low platelet count (8000 and 29,000 µL, respectively), giant platelets and Döhle body-like granulocyte inclusion bodies. The mother had a high creatinine level (15.4 mg/dL) and normal liver enzyme levels. MYH9 genetic analysis identified a heterozygous mutation, c.101T>A, p.Val34Glu at exon 2 in both patients. These clinical and laboratory findings were consistent with a diagnosis of an MYH9-related disorder with different phenotypes observed in the same family. MYH9-related disorders were recognised in 2003, but were often misdiagnosed as immune thrombocytopenia, and hence, they have rarely been reported in Taiwan.


Assuntos
Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Mutação , Cadeias Pesadas de Miosina/genética , Púrpura Trombocitopênica Idiopática , Trombocitopenia/congênito , Adulto , Idoso , Biomarcadores/sangue , Plaquetas/patologia , Creatinina/sangue , Diagnóstico Diferencial , Feminino , Granulócitos/citologia , Granulócitos/patologia , Perda Auditiva Neurossensorial/sangue , Humanos , Corpos de Inclusão/patologia , Masculino , Pessoa de Meia-Idade , Relações Mãe-Filho , Fenótipo , Contagem de Plaquetas , Taiwan , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/genética
4.
Int J Hematol ; 112(5): 725-727, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32557126

RESUMO

Chemotherapy is the mainstay of treatment for advanced pancreatic cancer however, due to possible myelotoxicity, it is used with caution in patients with thrombocytopenia, especially when severe. TPO-receptor agonists have been employed for chemotherapy-induced thrombocytopenia, however treatment with TPO-receptor agonists to allow chemotherapy in patients with inherited thrombocytopenia has not been reported so far. We report the first successful use of eltrombopag to prevent chemotherapy-induced thrombocytopenia in a patient with MHY9-related disorder and pancreatic cancer. Treatment with eltrombopag allowed to attain a safe and stable platelet count for several months sufficient to permit chemotherapy and to allow the patient to undergo endoscopic placement of a biliary stent with no bleeding complications.


Assuntos
Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Cadeias Pesadas de Miosina , Neoplasias Pancreáticas/tratamento farmacológico , Pirazóis/uso terapêutico , Trombocitopenia/tratamento farmacológico , Trombocitopenia/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzoatos/farmacologia , Perda Sanguínea Cirúrgica/prevenção & controle , Endoscopia do Sistema Digestório , Feminino , Humanos , Hidrazinas/farmacologia , Neoplasias Pancreáticas/cirurgia , Contagem de Plaquetas , Pirazóis/farmacologia , Receptores de Trombopoetina/agonistas , Trombocitopenia/sangue , Trombocitopenia/congênito
6.
PLoS One ; 15(5): e0233096, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32421725

RESUMO

Congenital cytomegalovirus (cCMV) infection is the most common intrauterine infection. A non-specific immune response is the first line of host defense mechanism against human cytomegalovirus (HCMV). There is limited data on associations between Single Nucleotide Polymorphisms (SNPs) in genes involving innate immunity and the risk and clinical manifestation of cCMV infection. The aim of the study was to investigate association between selected SNPs in genes encoding cytokines and cytokine receptors, and predisposition to cCMV infection including symptomatic course of disease and symptoms. A panel of eight SNPs: IL1B rs16944, IL12B rs3212227, IL28B rs12979860, CCL2 rs1024611, DC-SIGN rs735240, TLR2 rs5743708, TLR4 rs4986791, TLR9 rs352140 was analyzed in 233 infants (92 cCMV-infected and 141 healthy controls). Associations between genotyped SNPs and predisposition to cCMV infection and symptoms were analyzed. The association analysis was performed using SNPStats software. No statistically significant association was found between any genotyped SNPs and predisposition to cCMV infection and symptomatic course of disease. In relation to particular symptoms, polymorphism of IL12B rs3212227 was linked to decreased risk of prematurity (OR = 0.37;95%CI,0.14-0.98;p = 0.025), while polymorphism of IL1B rs16944 was linked to reduced risk of splenomegaly (OR = 0.36;95%CI,0.14-0.98; p = 0.034) in infants with cCMV infection. An increased risk of thrombocytopenia was associated with IL28B rs12979860 polymorphism (OR = 2.55;95%CI,1.03-6.32;p = 0.042), while hepatitis was associated with SNP of TLR4rs4986791 (OR = 7.80;95%CI,1.49-40,81; p = 0.024). This is the first study to demonstrate four new associations between SNPs in selected genes (IL1B, IL12B, IL28B, TLR4) and particular symptoms in cCMV disease. Further studies on the role of SNPs in the pathogenesis of cCMV infection and incorporation of selected SNPs in the clinical practice might be considered in the future.


Assuntos
Infecções por Citomegalovirus/genética , Interferons/genética , Interleucina-12/genética , Interleucina-1beta/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor 4 Toll-Like/genética , Adulto , Infecções por Citomegalovirus/virologia , Feminino , Frequência do Gene/genética , Genótipo , Técnicas de Genotipagem , Humanos , Masculino , Trombocitopenia/genética , Trombocitopenia/virologia
7.
Rev. cuba. hematol. inmunol. hemoter ; 36(1): e1125, ene.-mar. 2020.
Artigo em Espanhol | LILACS, CUMED | ID: biblio-1126540

RESUMO

Introducción: La trombocitopenia con ausencia de radios es un síndrome genético poco frecuente. Se caracteriza por la ausencia bilateral de radios con presencia de ambos pulgares y trombocitopenia. Pueden estar presentes, además, malformaciones en miembros inferiores, cardiovasculares, gastrointestinales, neurológicas y vasculares. Objetivo: Analizar los aspectos genéticos moleculares más recientes del síndrome de trombocitopenia. Métodos: Se realizó una revisión de la literatura en inglés y español, a través del sitio web PubMed y el motor de búsqueda Google académico, de artículos publicados en los últimos 10 años. Se hizo un análisis y resumen de la bibliografía revisada. Análisis y síntesis de la información: El patrón de herencia de la enfermedad es autosómico recesivo, un heterocigótico compuesto por un alelo nulo del gen RBM8A, localizado en el locus 1q21.1 y la presencia de un polimorfismo de simple nucleótido en regiones no codificantes en el otro alelo. Este gen codifica la proteína Y14, la cual es uno de los cuatro componentes del complejo de unión de exones, complejo multiproteico que se une al ARNm y que, una vez finalizado el empalme, interviene en la eficiencia de la traducción y la degradación del ARNm que presenten codones de terminación prematura. Conclusiones: La trombocitopenia es la primera enfermedad en el humano en la que se describe un defecto en una subunidad del complejo de unión de exones. A pesar del avance en los últimos años en el conocimiento de las bases moleculares de la enfermedad, aún son necesarias nuevas investigaciones para explicar la relación entre el gen RBM8 y las manifestaciones esqueléticas(AU)


Introduction: Thrombocytopenia with absent radii is a rare genetic syndrome, characterized by bilateral absence of the radii with the presence of both thumbs and thrombocytopenia. In addition, malformations may be present, involving the lower limbs, as well as the cardiovascular, gastrointestinal, neurological, and vascular systems. Objective: To analyze the most recent molecular genetic aspects of thrombocytopenia syndrome. Methods: A review of the literature in English and in Spanish was carried out, in the PubMed website and using the search engine of Google Scholar, for articles published in the last ten years. We performed analysis and summary of the reviewed bibliography. Information analysis and synthesis: The disease has an autosomal recessive inheritance pattern, a heterozygote composed of a null allele of the RBM8A gene, located at the 1q21.1 locus and the presence of a single nucleotide polymorphism in non-coding regions in the other allele. This gene encodes the Y14 protein, which is one of the four components of the exon-binding complex, a multiprotein complex that binds to mRNA and that, once splicing is complete, intervenes in the efficiency of translation and degradation of mRNA that have premature termination condons. Conclusions: Thrombocytopenia is the first disease in humans in which a defect in a subunit of the exon binding complex was described. Despite the advance in recent years in understanding the molecular basis of the disease, new research is still necessary to explain the relationship between the RBM8 gene and skeletal manifestations(AU)


Assuntos
Humanos , Masculino , Feminino , Trombocitopenia/genética , Trombocitopenia/epidemiologia , Literatura de Revisão como Assunto
8.
J Biotechnol ; 311: 44-48, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32109542

RESUMO

Rare genetic diseases and syndromes may appear with unique features in some patients. In genetically-solved cases, this situation indicates a phenotypic expansion of the syndrome with additional features (i.e. the disease-associated gene gives rise to unusual clinical presentation). However, this situation can also hide a multilocus pathogenic variation that cannot be solved genetically except by a massive sequencing approach, such as exome sequencing. Here we describe the case of a child with bilateral radial aplasia, transient thrombocytopenia and anemia, cow's milk intolerance, hypospadias, facial dysmorphism, mild hypothyroidism and umbilical and inguinal hernia. Bilaterally absent radius, presence of thumbs and low platelet count are pathognomonic of thrombocytopenia absent radius (TAR) syndrome, but the child also showed other features beyond those reported in the literature. Since various diseases resembling the proband's phenotype required differential diagnosis, clinical exome sequencing was performed. The results showed compound heterozygous mutations in the RBM8A gene, confirming the suspicion of TAR syndrome. A truncating heterozygous variant in the DUOX2 gene, known to be associated with transient thyroid dyshormonogenesis type 6 (TDH6), was also detected and may explain the proband's mild hypothyroidism.


Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/genética , Trombocitopenia/genética , Deformidades Congênitas das Extremidades Superiores/genética , Hipotireoidismo Congênito/genética , Testes Genéticos , Humanos , Lactente , Masculino , Mutação/genética , Fenótipo , Proteínas de Ligação a RNA/genética , Rádio (Anatomia)
9.
Nat Commun ; 11(1): 356, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953383

RESUMO

Glycosylation is critical to megakaryocyte (MK) and thrombopoiesis in the context of gene mutations that affect sialylation and galactosylation. Here, we identify the conserved B4galt1 gene as a critical regulator of thrombopoiesis in MKs. ß4GalT1 deficiency increases the number of fully differentiated MKs. However, the resulting lack of glycosylation enhances ß1 integrin signaling leading to dysplastic MKs with severely impaired demarcation system formation and thrombopoiesis. Platelets lacking ß4GalT1 adhere avidly to ß1 integrin ligands laminin, fibronectin, and collagen, while other platelet functions are normal. Impaired thrombopoiesis leads to increased plasma thrombopoietin (TPO) levels and perturbed hematopoietic stem cells (HSCs). Remarkably, ß1 integrin deletion, specifically in MKs, restores thrombopoiesis. TPO and CXCL12 regulate ß4GalT1 in the MK lineage. Thus, our findings establish a non-redundant role for ß4GalT1 in the regulation of ß1 integrin function and signaling during thrombopoiesis. Defective thrombopoiesis and lack of ß4GalT1 further affect HSC homeostasis.


Assuntos
Galactosiltransferases/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Homeostase , Integrina beta1/metabolismo , Trombopoese/fisiologia , Animais , Plaquetas/metabolismo , Plaquetas/patologia , Adesão Celular , Diferenciação Celular , Quimiocina CXCL12/metabolismo , Colágeno , Modelos Animais de Doenças , Fibronectinas , Galactosiltransferases/genética , Predisposição Genética para Doença , Hemorragia/genética , Hemorragia/metabolismo , Hemorragia/patologia , Integrina beta1/genética , Laminina , Ligantes , Megacariócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Transdução de Sinais , Trombocitopenia/genética , Trombocitopenia/metabolismo , Trombocitopenia/patologia , Trombopoese/genética , Trombopoetina/sangue
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 60-63, 2020 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-31922599

RESUMO

OBJECTIVE: To explore the molecular basis for a pedigree affected with May-Hegglin anomaly (MHA). METHODS: Peripheral blood samples were collected and subjected to DNA extraction. Exons 1, 10, 16, 24, 25, 26, 30, 31, 33, 38 and 40 and flanking sequences of the MYH9 gene were subjected to PCR amplification and Sanger sequencing. Changes in protein expression were determined by an indirect immunofluorescence assay. Platelet aggregation function of the proband was assessed by thromboelastogram. RESULTS: The proband and his second son both carried a heterozygous 5521G>A (GAG to AAG) missense variant in exon 38 of the MYH9 gene, leading to p.Glu1841Lys substitution at position 1841 of amino acid sequence. Immunofluorescence showed inclusions containing NMMHC-II A. Thromboelastogram suggested enhanced platelet aggregation function of the proband. CONCLUSION: The c.5521G>A variant of MYH9 gene has co-segregated with the phenotype of MHA in this pedigree. To assess the aggregation function of platelet by thromboelastogram can predict the risk of bleeding in MHA patients.


Assuntos
Perda Auditiva Neurossensorial , Cadeias Pesadas de Miosina , Trombocitopenia/congênito , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Mutação , Cadeias Pesadas de Miosina/genética , Linhagem , Trombocitopenia/genética
11.
Int Immunopharmacol ; 80: 106127, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31978798

RESUMO

BACKGROUND: The increased differentiation of T helper 17 cells (Th17) accelerates the development of immune thrombocytopenia (ITP), which is a common autoimmune disease with limited therapeutic methods. Recent studies have revealed that long non-coding RNAs (lncRNAs) play a critical role in autoimmune diseases, thus this study aims to investigate the effect of lncRNA GAS5 on the differentiation of Th17 cells in ITP. METHODS: The expression of GAS5 in peripheral blood mononuclear cells (PBMCs) of ITP patients and spleen tissues of ITP mice was measured by qRT-PCR. The percentage of Th17 cells in CD4+ cells was measured by flow cytometry. The combination between GAS5 and STAT3 was confirmed by RNA pull-down assay and RNA Binding Protein Immunoprecipitation (RIP). The ubiquitination of STAT3 was detected by ubiquitination assay and the interaction between STAT3 and TRAF6 was measured by Co-Immunoprecipitation (Co-IP). Finally, the effect of GAS5 on Th17 differentiation was investigated in vitro and in vivo using lentivirus (lenti)-GAS5. RESULTS: GAS5 expression was downregulated both in PBMCs of ITP patients and spleen tissues of ITP mice. Overexpression of GAS5 suppressed Th17 differentiation while had no effect on Treg differentiation in naïve CD4+ cells. RNA pull-down and RNA immunoprecipitation assays confirmed the interaction between GAS5 and STAT3. Further studies showed GAS5 accelerated the degradation of STAT3 via promoting TRAF6-mediated ubiquitination. Overexpressing GAS5 suppressed Th17 differentiation in vitro and alleviated ITP in vivo via reducing STAT3. CONCLUSION: LncRNA GAS5 inhibited Th17 differentiation through promoting the TRAF6-mediated ubiquitination of STAT3, thus relieving ITP.


Assuntos
RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/metabolismo , Células Th17/imunologia , Trombocitopenia/genética , Adulto , Animais , Estudos de Casos e Controles , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Proteólise , Baço/imunologia , Baço/patologia , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Trombocitopenia/sangue , Trombocitopenia/imunologia , Trombocitopenia/patologia , Ubiquitinação/genética
12.
Medicine (Baltimore) ; 99(4): e18887, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31977897

RESUMO

INTRODUCTION: MYH9-related disease (MYH9-RD) is a rare autosomal dominant disorder caused by mutations in MYH9, which is responsible for encoding nonmuscle myosin heavy chains IIA (NMMHCIIA). MYH9-RD is clinically characterized by congenital macrothrombocytopenia, granulocyte inclusions variably associated with the risk of developing progressive sensorineural deafness, cataracts and nephropathy. PATIENT CONCERNS: A 5-year-old boy had a history of a mild bleeding tendency and chronic thrombocytopenia, first identified at four months of age. No other family members were noted to have similar clinical features or hematologic disorders. DIAGNOSES: The boy was diagnosed with MYH9-RD. Light microscopic examination of peripheral blood films (Wright-Giemsa stain) showed marked platelet macrocytosis with giant platelets and basophilic Döhle-like inclusions in 83% of the neutrophils. Immunofluorescence analysis disclosed a type II pattern, manifested by neutrophils which contained several circle-to-oval shaped cytoplasmic NMMMHCA-positive granules. Sequencing analysis of MYH9-RD genes was carried out and revealed a novel missense mutation of c.97T>G (p.W33G) in the patient but not in his parents. INTERVENTION: No treatment is necessary. Recognition of MYH9-RD is important to Avoiding unnecessary and potentially harmful treatments. OUTCOMES: The patient's condition remained stable during the follow-up. CONCLUSIONS: As a result of identifying this missense mutation in this particular case, we have added c.97T>G (p.W33G) to the broad spectrum of potential MYH9 mutations.


Assuntos
Perda Auditiva Neurossensorial/genética , Trombocitopenia/congênito , Pré-Escolar , Imunofluorescência , Perda Auditiva Neurossensorial/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação de Sentido Incorreto , Neutrófilos/patologia , Trombocitopenia/diagnóstico , Trombocitopenia/genética
13.
FEBS Lett ; 594(1): 161-174, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31365757

RESUMO

Actinin-1 mutations cause dominantly inherited congenital macrothrombocytopenia (CMTP), with mutations in the actin-binding domain increasing actinin's affinity for F-actin. In this study, we examined nine CMTP-causing mutations in the calmodulin-like and rod domains of actinin-1. These mutations increase, to varying degrees, actinin's ability to bundle actin filaments in vitro. Mutations within the calmodulin-like domain decrease its thermal stability slightly but do not dramatically affect calcium binding, with mutant proteins retaining calcium-dependent regulation of filament bundling in vitro. The G764S and E769K mutations increase cytoskeletal association of actinin in cells, and all mutant proteins colocalize with F-actin in cultured HeLa cells. Thus, CMTP-causing actinin-1 mutations outside the actin-binding domain also increase actin association, suggesting a common molecular mechanism underlying actinin-1 related CMTP.


Assuntos
Actinina/genética , Mutação de Sentido Incorreto , Trombocitopenia/genética , Citoesqueleto de Actina/metabolismo , Actinina/metabolismo , Animais , Sítios de Ligação , Células CHO , Cálcio/metabolismo , Cricetinae , Cricetulus , Células HeLa , Humanos , Ligação Proteica
14.
Platelets ; 31(2): 276-279, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31389738

RESUMO

Chronic hemorrhagic diathesis in patients showing normal levels of plasmatic clotting factors strongly suggests for congenital platelet disorders. We report on a pediatric patient (male, 3 years, D1) with mild bleeding. A sibling (D2), his mother (D3) and father (D4) were included for laboratory investigation. Platelet counts in D1, D2 and D4 indicated mild thrombocytopenia (100 Gpt/L). D1 and D3 platelets showed significantly diminished aggregation response on arachidonic acid and U46619 stimulation. Immunostaining for platelet proteins on blood smears of D1 and D2 indicated defects in ß1-tubulin. Exon sequencing of TBXA2R and TUBB1 revealed heterozygosity for the novel TBXA2R*c.908T>C (p.L303P) mutation in D1 and D3. TUBB1 was either wild type (D2, D3) or heterozygous (D1, D4) for the common polymorphism TUBB1*c.920G>A (rs6070697; p.R307H). In conclusion, the bleeding phenotype of the index patient can be explained by a diminished platelet function caused by the TBXA2R*c.908T>C mutation inherited from the mother and a mild thrombocytopenia with unknown molecular basis that is inherited from the father.


Assuntos
Transtornos Plaquetários/genética , Hemorragia/genética , Receptores de Tromboxano A2 e Prostaglandina H2/genética , Trombocitopenia/congênito , Trombocitopenia/genética , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Adulto , Ácido Araquidônico/farmacologia , Transtornos Plaquetários/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Pré-Escolar , Feminino , Hemorragia/metabolismo , Transtornos Hemorrágicos/genética , Transtornos Hemorrágicos/metabolismo , Heterozigoto , Humanos , Masculino , Mutação , Fenótipo , Contagem de Plaquetas , Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo , Trombocitopenia/metabolismo , Tubulina (Proteína)/sangue , Tubulina (Proteína)/genética
15.
Platelets ; 31(2): 198-205, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30885035

RESUMO

MicroRNAs (miRNAs) are small non-coding RNAs involved in the regulation of gene expression. Dysregulated expression of several miRNAs has been found in primary immune thrombocytopenia (ITP) suggesting that miRNAs are likely involved in the pathogenesis of ITP. We aimed to explore the differential expression of miRNAs in patients with ITP before and after starting treatment with thrombopoietin-receptor agonists (TPO-RAs) to clarify their roles in the pathophysiology of ITP, and as potential diagnostic and prognostic markers of this disorder.We performed a profiling study where 179 miRNAs were analyzed in eight ITP patients before and during treatment with TPO-RAs and in eight controls using miRNA PCR panel; 81 miRNAs were differentially expressed in ITP patients compared to controls, and 14 miRNAs showed significant changes during TPO-RA-treatment. Ten miRNAs were selected for validation that was performed in 23 patients and 22 controls using droplet digital PCR. Three miRNAs were found to be differentially expressed in ITP patients before TPO-RA-treatment compared to controls: miR-199a-5p was down-regulated (p = 0.0001), miR-33a-5p (p = 0.0002) and miR-195-5p (p = 0.035) were up-regulated. Treatment with TPO-RAs resulted in changes in six miRNAs including miR-199a-5p (p = 0.001), miR-33a-5p (p = 0.003), miR-382-5p (p = 0.004), miR-92b-3p (p = 0.005), miR-26a-5p (p = 0.008) and miR-221-3p (p = 0.023); while miR-195-5p remained unchanged and significantly higher than in controls, despite the increase in the platelet count, which may indicate its possible role in the pathophysiology of ITP. Regression analysis revealed that pre-treatment levels of miR-199a-5p and miR-221-3p could help to predict platelet response to TPO-RA-treatment. ROC curve analysis showed that the combination of miR-199a-5p and miR-33a-5p could distinguish patients with ITP from controls with AUC of 0.93.This study identifies a number of differentially expressed miRNAs in ITP patients before and after initiation of TPO-RAs with potential roles in the pathophysiology, as well as with a possible utility as diagnostic and prognostic biomarkers. These interesting findings deserve further exploration and validation in future studies.


Assuntos
MicroRNA Circulante/sangue , Receptores de Trombopoetina/agonistas , Trombocitopenia/genética , Adulto , Biomarcadores Farmacológicos , Plaquetas/metabolismo , MicroRNA Circulante/genética , MicroRNA Circulante/metabolismo , Estudos de Coortes , Biologia Computacional , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , Contagem de Plaquetas , Prognóstico , Curva ROC , Análise de Regressão , Trombocitopenia/tratamento farmacológico , Trombocitopenia/metabolismo , Trombocitopenia/fisiopatologia , Regulação para Cima
16.
Clin Chim Acta ; 501: 131-135, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31678577

RESUMO

BACKGROUND: Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that leads to renal failure in childhood or adolescence. NPHP and the related syndromes have been termed 'ciliopathies' because most NPHP gene products localize to the cilium or its associated structures. METHODS: Here, we report a 2-year and 11-month-old Chinese girl with end-stage renal disease (ESRD), severe anemia, thrombocytopenia and myocardial hypertrophy. We performed trio-whole-exome sequencing to identify the causative variant of this patient. RESULTS: We identified an unreported compound heterozygous mutation (c.2420dupT, p.Thr808Aspfs*2 and c.1973-1G > A) in ANKS6 in the proband. The frameshift mutation c.2420dupT of ANKS6 was inherited from the proband's unaffected father and the splicing mutation c.1973-1G > A of ANKS6 was inherited from the proband's unaffected mother. Homozygous mutation in ANKS6 leads to NPHP16 (OMIM#615382) and this is the first case with a compound heterozygous mutation in the NPHP16 gene. CONCLUSION: We have identified a patient with ANKS6 variants in the East-Asian population for the first time. This case report expands the clinical and genetic spectra of NPHP and emphasizes the usefulness of whole-exome sequencing for genetic diagnosis of kidney disease.


Assuntos
Doenças Renais Císticas/genética , Falência Renal Crônica/genética , Mutação , Proteínas Nucleares/genética , Sequenciamento Completo do Exoma , Anemia/genética , Pré-Escolar , China , Feminino , Humanos , Lactente , Trombocitopenia/genética
18.
J Pediatr Hematol Oncol ; 42(3): e188-e192, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30720677

RESUMO

May-Hegglin anomaly (MHA) is a rare autosomal dominant disorder caused by a mutation in the myosin heavy chain 9 (MYH9) gene. MHA patients have variable clinical manifestations including thrombocytopenia, renal injury, hearing impairment, and cataracts. We describe a 25-year-old man with isolated thrombocytopenia initially. He experienced recurrent seizures with stable thrombocytopenia after the first seizures related to intracranial hemorrhage. He was identified a novel c.3452C>T mutation by targeted exome sequencing. If a patient with thrombocytopenia shows recurrent seizures as well as renal, hearing, visual symptoms, MHA should be suspected and the targeted exome sequencing is considered an effective diagnostic tool.


Assuntos
Perda Auditiva Neurossensorial/genética , Cadeias Pesadas de Miosina/genética , Convulsões/genética , Trombocitopenia/congênito , Adulto , Perda Auditiva Neurossensorial/complicações , Humanos , Masculino , Mutação de Sentido Incorreto , Trombocitopenia/complicações , Trombocitopenia/genética , Sequenciamento Completo do Exoma
19.
Artigo em Inglês | MEDLINE | ID: mdl-31836590

RESUMO

Thrombocytopenia-absent radii (TAR) syndrome, characterized by neonatal thrombocytopenia and bilateral radial aplasia with thumbs present, is typically caused by the inheritance of a 1q21.1 deletion and a single-nucelotide polymorphism in RBM8A on the nondeleted allele. We evaluated two siblings with TAR-like dysmorphology but lacking thrombocytopenia in infancy. Family NCI-107 participated in an IRB-approved cohort study and underwent comprehensive clinical and genomic evaluations, including aCGH, whole-exome, whole-genome, and targeted sequencing. Gene expression assays and electromobility shift assays (EMSAs) were performed to evaluate the variant of interest. The previously identified TAR-associated 1q21.1 deletion was present in the affected siblings and one healthy parent. Multiple sequencing approaches did not identify previously described TAR-associated SNPs or mutations in relevant genes. We discovered rs61746197 A > G heterozygosity in the parent without the deletion and apparent hemizygosity in both siblings. rs61746197 A > G overlaps a RelA-p65 binding motif, and EMSAs indicate the A allele has higher transcription factor binding efficiency than the G allele. Stimulation of K562 cells to induce megakaryocyte differentiation abrogated the shift of both reference and alternative probes. The 1q21.1 TAR-associated deletion in combination with the G variant of rs61746197 on the nondeleted allele is associated with a TAR-like phenotype. rs61746197 G could be a functional enhancer/repressor element, but more studies are required to identify the specific factor(s) responsible. Overall, our findings suggest a role of rs61746197 A > G and human disease in the setting of a 1q21.1 deletion on the other chromosome.


Assuntos
Anormalidades Múltiplas/genética , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Megalencefalia/genética , Trombocitopenia/genética , Deformidades Congênitas das Extremidades Superiores/genética , Adolescente , Adulto , Alelos , Criança , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Família , Feminino , Heterozigoto , Humanos , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Proteínas de Ligação a RNA/genética , Rádio (Anatomia) , Irmãos , Síndrome
20.
Hematology Am Soc Hematol Educ Program ; 2019(1): 367-372, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808873

RESUMO

Lower-risk myelodysplastic syndromes are defined using prognostic scoring systems that incorporate data on bone marrow blast percentage, degree and numbers of cytopenias, and cytogenetic abnormalities. Increasingly, these are incorporating molecular abnormalities to further refine risk. Therapy is geared toward predominating cytopenias, with erythropoiesis-stimulating agents luspatercept and lenalidomide used to ameliorate anemia, romiplostim and eltrombopag tackling thrombocytopenia, and hypomethylating agents and antithymocyte globulin palliating pancytopenia. Newer agents on the horizon are abrogating the downstream sequelae of specific molecular mutations. One challenge for the future is in further modifying response criteria to align with improvements that are clinically meaningful to patients.


Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Soro Antilinfocitário/uso terapêutico , Benzoatos/uso terapêutico , Células da Medula Óssea , Hematínicos/uso terapêutico , Hidrazinas/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Lenalidomida/uso terapêutico , Síndromes Mielodisplásicas , Pirazóis/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Feminino , Humanos , Mutação , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Fatores de Risco , Trombocitopenia/tratamento farmacológico , Trombocitopenia/genética , Trombocitopenia/metabolismo , Trombocitopenia/patologia
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