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1.
Medicine (Baltimore) ; 98(36): e17070, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490406

RESUMO

Periventricular nodular heterotopia (PNH) is the most common type of epileptogenic neuronal migration disorder, and often presents with epilepsy and reading disability. The functional role of ectopic nodules has been widely studied. However, the associated structural cortical and subcortical volumetric alterations have not been well characterized. Moreover, it is unknown whether a correlation between volumetric changes and behavioral problems exists.40 subjects with bilateral PNH and 40 matched healthy controls were enrolled in this study. The total cerebral, gray matter, white matter, and cerebrospinal fluid (CSF) volumes were compared between the two groups. Furthermore, structural and functional correlations were evaluated between volumetric changes and reading disability.There were no significant differences detected in total cerebral, gray matter or CSF volumes between the two groups, but there was a significant trend of larger gray-matter volume in PNH. Specifically, smaller white matter volumes were found in the PNH patients. Moreover, the volume of white matter was negatively related to time in the digit rapid naming task and a similar but insignificant trend was seen between the volume of gray matter and backward digit span.These findings suggest that reading disability exists in our sample of bilateral PNH. Periventricular nodules would have normally migrated to the overlying cortex. However, the total cerebral, gray matter, and CSF volumes were unaffected. Alterations in neuronal migration may have an impact in the white matter associated reading dysfluency, that is, visually normal.


Assuntos
Córtex Cerebral/diagnóstico por imagem , Dislexia/diagnóstico por imagem , Dislexia/etiologia , Heterotopia Nodular Periventricular/complicações , Heterotopia Nodular Periventricular/diagnóstico por imagem , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Filaminas/genética , Humanos , Imagem por Ressonância Magnética , Masculino , Heterotopia Nodular Periventricular/genética , Adulto Jovem
3.
Int Braz J Urol ; 45(5): 916-924, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31268639

RESUMO

OBJECTIVE: This study aims to investigate the association of filamin A with the function and morphology of prostate cancer (PCa) cells, and explore the role of filamin A in the development of PCa, in order to analyze its significance in the evolvement of PCa. MATERIALS AND METHODS: A stably transfected cell line, in which filamin A expression was suppressed by RNA interference, was first established. Then, the effects of the suppression of filamin A gene expression on the biological characteristics of human PCa LNCaP cells were observed through cell morphology, in vitro cell growth curve, soft agar cloning assay, and scratch test. RESULTS: A cell line model with a low expression of filamin A was successfully constructed on the basis of LNCaP cells. The morphology of cells transfected with plasmid pSilencer-filamin A was the following: Cells were loosely arranged, had less connection with each other, had fewer tentacles, and presented a fibrous look. The growth rate of LNCap cells was faster than cells transfected with plasmid pSilencer-filamin A (P<0.05). The clones of LNCap cells in the soft agar cloning assay was significantly fewer than that of cells stably transfected with plasmid pSilencer-filamin A (P<0.05). Cells stably transfected with plasmid pSilencer-filamin A presented with a stronger healing and migration ability compared to LNCap cells (healing rate was 32.2% and 12.1%, respectively; P<0.05). CONCLUSION: The expression of the filamin A gene inhibited the malignant development of LNCap cells. Therefore, the filamin A gene may be a tumor suppressor gene.


Assuntos
Filaminas/análise , Filaminas/fisiologia , Neoplasias da Próstata/patologia , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Colorimetria/métodos , Filaminas/genética , Formazans , Humanos , Masculino , Plasmídeos , Neoplasias da Próstata/genética , Sais de Tetrazólio , Fatores de Tempo , Transfecção/métodos , Cicatrização/fisiologia
4.
Emerg Microbes Infect ; 8(1): 934-945, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31237474

RESUMO

Cytoskeletal rearrangement and acute cytotoxicity occur in Vibrio vulnificus-infected host cells. RtxA1 toxin, a multifunctional autoprocessing repeats-in-toxin (MARTX), is essential for the pathogenesis of V. vulnificus and the programmed necrotic cell death. In this study, HeLa cells expressing RtxA1 amino acids 1491-1971 fused to GFP were observed to be rounded. Through yeast two-hybrid screening and subsequent immunoprecipitation validation assays, we confirmed the specific binding of a RtxA11491-1971 fragment with host-cell filamin A, an actin cross-linking scaffold protein. Downregulation of filamin A expression decreased the cytotoxicity of RtxA1 toward host cells. Furthermore, the phosphorylation of JNK and p38 MAPKs was induced by the RtxA1-filamin A interaction during the toxin-mediated cell death. However, the phosphorylation of these MAPKs was not observed during the RtxA1 intoxication of filamin A-deficient M2 cells. In addition, the depletion of pak1, which appeared to be activated by the RtxA1-filamin A interaction, inhibited RtxA1-induced phosphorylation of JNK and p38, and the cells treated with a pak1 inhibitor exhibited decreased RtxA1-mediated cytoskeletal rearrangement and cytotoxicity. Thus, the binding of filamin A by the RtxA11491-1971 domain appears to be a requisite to pak1-mediated MAPK activation, which contributes to the cytoskeletal reorganization and host cell death.


Assuntos
Toxinas Bacterianas/metabolismo , Citoesqueleto/metabolismo , Filaminas/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Vibrioses/metabolismo , Vibrio vulnificus/metabolismo , Quinases Ativadas por p21/metabolismo , Motivos de Aminoácidos , Toxinas Bacterianas/toxicidade , Morte Celular , Citoesqueleto/genética , Filaminas/genética , Células HeLa , Interações Hospedeiro-Patógeno , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Ligação Proteica , Vibrioses/genética , Vibrioses/microbiologia , Vibrioses/fisiopatologia , Vibrio vulnificus/química , Vibrio vulnificus/genética , Quinases Ativadas por p21/genética
6.
Epilepsy Res ; 153: 49-58, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30986657

RESUMO

The Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are highly expressed in the Central Nervous Systems, where they are responsible for the Ih current. Together with specific accessory proteins, these channels finely regulate neuronal excitability and discharge activity. In the last few years, a substantial body of evidence has been gathered showing that modifications of Ih can play an important role in the pathogenesis of epilepsy. However, the extent to which HCN dysfunction is spread among the epileptic population is still unknown. The aim of this work is to evaluate the impact of genetic mutations potentially affecting the HCN channels' activity, using a NGS approach. We screened a large cohort of patients with epilepsy of unknown etiology for mutations in HCN1, HCN2 and HCN4 and in genes coding for accessory proteins (MiRP1, Filamin A, Caveolin-3, TRIP8b, Tamalin, S-SCAM and Mint2). We confirmed the presence of specific mutations of HCN genes affecting channel function and predisposing to the development of the disease. We also found several previously unreported additional genetic variants, whose contribution to the phenotype remains to be clarified. According to these results and data from literature, alteration of HCN1 channel function seems to play a major role in epilepsy, but also dysfunctional HCN2 and HCN4 channels can predispose to the development of the disease. Our findings suggest that inclusion of the genetic screening of HCN channels in diagnostic procedures of epileptic patients should be recommended. This would help pave the way for a better understanding of the role played by Ih dysfunction in the pathogenesis of epilepsy.


Assuntos
Epilepsia/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Mutação/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Caderinas/genética , Proteínas de Transporte/genética , Caveolina 3/genética , Estudos de Coortes , Eletroencefalografia , Saúde da Família , Feminino , Filaminas/genética , Testes Genéticos , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Receptores Citoplasmáticos e Nucleares/genética
7.
Oncol Rep ; 41(6): 3424-3434, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002357

RESUMO

Several studies have demonstrated that calpain­1 is involved in a variety of pathophysiological processes, including tumorigenesis. However, the clinical relevance and role of calpain­1 in colorectal cancer (CRC) are unclear. Filamin A (FLNA) is an actin­binding protein that participates in cancer progression and can be cleaved by calpain­1. In the present study, the protein expression levels of calpain­1 and FLNA were detected by immunohistochemistry in 467 matched cancerous and paracancerous tissues from patients with CRC. The staining results and the clinicopathological characteristics of the patients were comprehensively analyzed. A high expression level of calpain­1 was strongly associated with age, metastasis, Dukes stage and survival time but not with sex, histologic grade, tumour location or tumor size. By contrast, a low expression level of FLNA was significantly associated with tumor size, histological grade, metastasis, Dukes stage and survival time, but not with age, sex, or tumor location. Kaplan­Meier survival analysis demonstrated that patients with calpain­1 overexpression had a shorter mean overall survival (OS) than patients with lower levels of calpain­1 expression. Unlike high levels of calpain­1, high levels of FLNA were associated with longer OS than lower levels of FLNA expression. Furthermore, calpain­1 expression was inversely correlated with FLNA expression. The relationship between calpain­1 and FLNA was further confirmed using CRC cell lines in vitro. When calpain­1 expression decreased in CRC cells, FLNA expression increased. Furthermore, calpain­1 knockdown in CRC cells resulted in decreased proliferation, colony formation, migration and invasion. The present findings suggest that calpain­1 overexpression predicted a poor outcome in patients with CRC and promoted tumor progression, possibly via FLNA downregulation.


Assuntos
Biomarcadores Tumorais/genética , Calpaína/genética , Neoplasias Colorretais/genética , Filaminas/genética , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia
8.
Mol Genet Genomic Med ; 7(5): e648, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30916490

RESUMO

BACKGROUND: A family with skeletal and craniofacial anomalies is presented. Whole-exome sequencing (WES) analysis indicated a diagnosis of Larsen syndrome, although their clinical presentation does not include the hallmark joint dislocations typically observed in Larsen syndrome. METHODS: Patient consent for the sharing of de-identified clinical and genetic information, along with use of photographs for publication, was obtained. WES and variant segregation analysis by WES were performed by commercial laboratory, GeneDx (Gaithersburg, MD), on peripheral blood samples from the proband, her brother, and her parents using methods detailed on their website for test XomeDx Whole Exome Sequencing Trio (https://www.genedx.com/test-catalog/available-tests/xomedx-whole-exome-sequencing-trio/). WES uses next-generation sequencing (NGS) technology to assess for variants within the coding regions, or exons, of approximately 23,000 genes. For the FLNB gene (NM_001457.3), 100% of the coding region was covered at a minimum of 10x. GeneDx uses Sanger sequencing to confirm NGS variants. RESULTS: WES revealed a heterozygous pathogenic variant, p.Glu227Lys (c.679G>A), in the FLNB gene in three out of the four family members tested. This variant is associated with Larsen syndrome, a skeletal dysplasia condition with a wide range of phenotypic variability that usually includes congenital joint dislocations. CONCLUSION: This is a highly unusual presentation of Larsen syndrome in which the identifying hallmark trait is absent in the patients' phenotypes.


Assuntos
Luxações Articulares/genética , Osteocondrodisplasias/genética , Fenótipo , Adulto , Feminino , Filaminas/genética , Humanos , Lactente , Recém-Nascido , Luxações Articulares/patologia , Masculino , Osteocondrodisplasias/patologia , Linhagem
9.
Rev Esp Cardiol (Engl Ed) ; 72(4): 333-340, 2019 Apr.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30792015

RESUMO

Dilated cardiomyopathy is inherited in nearly 50% of cases. More than 90 genes have been associated with this disease, which is one of the main causes of heart transplant and has been associated with an increased risk of sudden cardiac death. Risk stratification in these patients continues to be challenging. The identification of the specific etiology of the disease is very useful for the early detection of mutation carriers. Genetic study often provides prognostic information and can determine the therapeutic approach. Wide phenotypic variability is observed depending on the mutated gene, the type of mutation, and the presence of additional genetic and environmental factors.


Assuntos
Cardiomiopatia Dilatada/genética , Testes Genéticos/métodos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas do Citoesqueleto/genética , Desmossomos/genética , Filaminas/genética , Genes , Genes Mitocondriais/genética , Humanos , Proteína 2 de Membrana Associada ao Lisossomo/genética , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Prognóstico , Proteínas de Ligação a RNA/genética , Medição de Risco , Sarcômeros/genética
11.
Eur J Pediatr ; 178(2): 121-129, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30547349

RESUMO

The filamin A gene (FLNA) on Xq28 encodes the filamin A protein. Mutation in FLNA causes a wide spectrum of disease including skeletal dysplasia, neuronal migration abnormality, cardiovascular malformation, intellectual disability and intestinal obstruction. Recently, childhood-onset interstitial lung disease associated with a range of FLNA mutations has been recognised and reported. We document our personal experience of this emerging disorder and compile a comprehensive overview of clinical features and molecular changes in all identifiable published cases. Reviewing the emerging dataset, we underline this unanticipated phenotypic consequence of pathogenic FLNA mutation-associated pulmonary disease.Conclusion: From the emerging data, we suggest that while reviewing complex cases with a sustained oxygen requirement against a clincial background of cardiac concerns or intestinal obstruction to have a high index of suspicion for FLNA related pathology and to instigate early MRI brain scan and FLNA mutation analysis. What is Known: • FLNA gene on Xq28 encodes the filamin A protein and mutation therein is associated with variable phenotypes depending on its nature of mutation. • Loss-of-function mutation of filamin A is associated with X-linked inherited form of periventricular nodular heterotopia with or without epilepsy with most individuals affected being female. There is a recently recognised associated respiratory phenotype. What is New: • The respiratory phenotype in the form of childhood interstitial lung disease is a recently recognised clinical consequence of loss-of-function FLNA mutation. • Rare male patients with loss-of-function FLNA mutation-associated lung disease with residual protein function can survive into infancy with a severe form of the phenotype.


Assuntos
Filaminas/genética , Doenças Pulmonares Intersticiais/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Pulmão/patologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/terapia , Imagem por Ressonância Magnética , Masculino , Mutação , Heterotopia Nodular Periventricular/genética , Fenótipo , Tomografia Computadorizada por Raios X , Ultrassonografia Doppler Transcraniana
12.
Medicine (Baltimore) ; 97(50): e13033, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30557962

RESUMO

RATIONALE: Mesenchymal stem cells (MSC) play a crucial role in both the maintenance of pulmonary integrity and the pathogenesis of lung disease. Lung involvement has been reported in patients with the filamin A (FLNA) gene mutation. Considering FLNA's role in the intrinsic mechanical properties of MSC, we characterized MSCs isolated from FLNA-defective lung tissue, in order to define their pathogenetic role in pulmonary damage. PATIENT CONCERNS: A male infant developed significant lung disease resulting in emphysematous lesions and perivascular and interstitial fibrosis. He also exhibited general muscular hypotonia, bilateral inguinal hernia, and deformities of the lower limbs (pes tortus congenitalis and hip dysplasia). Following lobar resection, chronic respiratory failure occurred. DIAGNOSIS: Genetic testing was performed during the course of his clinical care and revealed a new pathogenic variant of the FLNA gene c.7391_7403del; (p.Val2464AlafsTer5). Brain magnetic resonance imaging revealed periventricular nodular heterotopia. INTERVENTIONS AND OUTCOMES: Surgical thoracoscopic lung biopsy was performed in order to obtain additional data on the pathological pulmonary features. A small portion of the pulmonary tissue was used for MSC expansion. Morphology, immunophenotype, differentiation capacity, and proliferative growth were evaluated. Bone marrow-derived mesenchymal stem cells (BM-MSC) were employed as a control. MSCs presented the typical MSC morphology and phenotype while exhibiting higher proliferative capacity (P <.001) and lower migration potential (P=.02) compared to control BM-MSC. LESSONS: The genetic profile and altered features of the MSCs isolated from FLNA-related pediatric lung tissue could be directly related to defects in cell migration during embryonic lung development and pulmonary damage described in FLNA-defective patients.


Assuntos
Filaminas/genética , Pneumopatias/genética , Células-Tronco Mesenquimais/patologia , Biópsia/métodos , Diferenciação Celular/genética , Humanos , Lactente , Itália , Pulmão/patologia , Pulmão/fisiopatologia , Pneumopatias/fisiopatologia , Masculino
14.
Front Immunol ; 9: 2852, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30568657

RESUMO

The integrin LFA-1 (CD11a/CD18) plays a critical role in the interaction of T cells with antigen presenting cells (APCs) to promote lymphocyte differentiation and proliferation. This integrin can be present either in a closed or in an open active conformation and its activation upon T-cell receptor (TCR) stimulation is a critical step to allow interaction with APCs. In this study we demonstrate that the serine/threonine kinase Ndr2 is critically involved in the initiation of TCR-mediated LFA-1 activation (open conformation) in T cells. Ndr2 itself becomes activated upon TCR stimulation and phosphorylates the intracellular integrin binding partner Filamin A (FLNa) at serine 2152. This phosphorylation promotes the dissociation of FLNa from LFA-1, allowing for a subsequent association of Talin and Kindlin-3 which both stabilize the open conformation of LFA-1. Our data suggest that Ndr2 activation is a crucial step to initiate TCR-mediated LFA-1 activation in T cells.


Assuntos
Filaminas/metabolismo , Antígeno-1 Associado à Função Linfocitária/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Animais , Antígenos CD18/imunologia , Antígenos CD18/metabolismo , Células Cultivadas , Proteínas do Citoesqueleto/imunologia , Proteínas do Citoesqueleto/metabolismo , Filaminas/genética , Filaminas/imunologia , Células HEK293 , Voluntários Saudáveis , Humanos , Células Jurkat , Ativação Linfocitária , Antígeno-1 Associado à Função Linfocitária/imunologia , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Mutação , Proteínas de Neoplasias/imunologia , Proteínas de Neoplasias/metabolismo , Fosforilação/imunologia , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Proteínas/genética , Receptores de Antígenos de Linfócitos T/imunologia , Serina/metabolismo , Linfócitos T/metabolismo , Talina/imunologia , Talina/metabolismo
15.
Medicine (Baltimore) ; 97(28): e11283, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29995760

RESUMO

RATIONALE: Frontometaphyseal dysplasia (FMD) is a dominant X-linked rare disease caused by mutations of FLNA. The distinctive features of FMD include skeletal dysplasia, facial dysmorphism, extremities anomalies, deafness, cleft palate and eye anterior segment anomalies, yet none of the complications, such as acro-osteolysis, keratitis, xerosis or poikiloderma, have been reported in FMD. PATIENT CONCERNS: A 29-year-old mother and her 7-year-old daughter, both presented with congenital glaucoma, craniofacial dysmorphism, xerosis and poikiloderma, were admitted to our hospital in 2011. Additionally, the mother also suffered from acro-osteolysis, keratitis, camptodactyly of hands and metastatic cutaneous squamous cell carcinoma (SCC) which turned out to be fatal 5 years later. In 2017, keratitis and acro-osteolysis were noticed in the daughter as well. Radiography showed bowed long bones with thickening cortex, and distal phalangeal osteolysis. DIAGNOSES: Whole genome sequencing (WGS) was conducted in 2016, resulting in 71491 single-nucleotide polymorphisms and 7616 indels shared by patients while the father was taken as control. A FLNA variant was classified likely pathogenic, supporting the diagnoses of FMD. In addition, though our patients' symptoms were highly consistent with xeroderma pigmentosum variant, a mild subtype of xeroderma pigmentosum (XP) with merely accumulated UV-induced lesions like xerosis and poikiloderma limited to sun-exposure sites, higher risks of cutaneous neoplasms and absence of classical XP features, WGS didn't find supportive genetical evidence, but 2 HERC2 variants were assigned highest suspicion in both XP and SCC by bioinformatical analyses. INTERVENTIONS: Anti-inflammatory treatment, sunscreens and moisturizers were administered. OUTCOMES: The daughter's cutaneous lesions developed slowly during the 6-year follow-up, but the keratitis seriously weakened her sight. LESSONS: To our knowledge, it's the first report of cases carrying FMD, keratitis, xerosis, poikiloderma and acro-osteolysis simultaneously, and 3 likely pathogenic variants were identified. Whole genome/exon sequencing is recommended as a common test for patients with rare phenotypes.


Assuntos
Carcinoma de Células Escamosas , Filaminas/genética , Testa/anormalidades , Osteocondrodisplasias , Neoplasias Cutâneas , Adulto , Assistência ao Convalescente/métodos , Amputação/métodos , Cegueira/etiologia , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Criança , Evolução Fatal , Feminino , Testa/fisiopatologia , Humanos , Extremidade Inferior/patologia , Extremidade Inferior/cirurgia , Mães , Mutação , Núcleo Familiar , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Osteocondrodisplasias/fisiopatologia , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Sequenciamento Completo do Genoma
16.
Rev. esp. cardiol. (Ed. impr.) ; 71(7): 545-552, jul. 2018. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-178580

RESUMO

Introducción y objetivos: La displasia valvular cardiaca ligada al cromosoma X es una cardiopatía congénita rara específica del sexo masculino y caracterizada principalmente por una degeneración mixomatosa de las válvulas auriculoventriculares con consecuencias hemodinámicas variables. Se debe a defectos genéticos en la filamina A (codificada por FLNA), una proteína de unión a actina de expresión ubicua que regula la organización del citoesqueleto. La pérdida de función de la filamina A también se ha asociado con manifestaciones neurológicas y del tejido conectivo a menudo simultáneas, y aparentemente las mutaciones en la primera mitad del dominio Rod 1 expresan el fenotipo cardiaco completo. En esta familia de nueva descripción, se ha contribuido a las correlaciones genotipo-fenotipo previas con un enfoque multidisciplinario. Métodos: La evaluación cardiológica, dismorfológica y genética de los miembros disponibles se complementó con estudios de la transcripción y de la inactivación del cromosoma X. Resultados: La nueva mutación de FLNA c.1066-3C>G cosegregaba con un fenotipo cardiaco aparentemente aislado y expresado en los varones, sin que hubiera un sesgo en el patrón de inactivación del cromosoma X en las mujeres portadoras. Esta variante resultó en una deleción dentro del marco de lectura de 8 residuos de aminoácidos cercanos a la región N-terminal de la proteína. Conclusiones: La pérdida de función parcial y no sometida a impronta del dominio Rod 1 proximal de la filamina A parece ser el mecanismo patogénico de la displasia valvular cardiaca, expresada en algunos casos con manifestaciones extracardiacas


Introduction and objectives: X-linked cardiac valvular dysplasia is a rare form of male-specific congenital heart defect mainly characterized by myxomatous degeneration of the atrioventricular valves with variable hemodynamic consequences. It is caused by genetic defects in FLNA-encoded filamin A, a widely expressed actin-binding protein that regulates cytoskeleton organization. Filamin A loss of function has also been associated with often concurring neurologic and connective tissue manifestations, with mutations in the first half of the Rod 1 domain apparently expressing the full cardiac phenotype. We contribute to previous genotype-phenotype correlations with a multidisciplinary approach in a newly-described family. Methods: Cardiologic, dysmorphologic, and genetic evaluation of available members were complemented with transcriptional and X-chromosome inactivation studies. Results: A novel FLNA mutation c.1066-3C>G cosegregated with a male-expressed, apparently isolated, cardiac phenotype with no skewed X-inactivation pattern in female carriers. This variant was shown to result in an in-frame deletion of 8 amino acid residues near the N-terminal region of the protein. Conclusions: A nonimprinted, partial loss of function of filamin A proximal Rod 1 domain seems to be the pathogenetic mechanism of cardiac valvular dysplasia, with some cases occasionally expressing associated extracardiac manifestations


Assuntos
Humanos , Masculino , Feminino , Prolapso das Valvas Cardíacas/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Filaminas/genética , Mutação/genética , Marcadores Genéticos , Cardiopatias Congênitas
17.
BMC Neurol ; 18(1): 79, 2018 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-29866061

RESUMO

BACKGROUND: Filamin C-related myofibrillar myopathies (MFM) are progressive skeletal myopathies with an autosomal dominant inheritance pattern. The conditions are caused by mutations of the filamin C gene (FLNC) located in the chromosome 7q32-q35 region. Genetic variations in the FLNC gene result in various clinical phenotypes. CASE PRESENTATION: We describe a 43-year-old woman who suffered filamin C-related MFM, with symptoms first presenting in the proximal muscles of the lower limbs and eventually spreading to the upper limbs and distal muscles. The patient's serum level of creatine kinase was mildly increased. Mildy myopathic changes in the electromyographic exam and moderate lipomatous alterations in lower limb MRI were found. Histopathological examination revealed increased muscle fiber size variability, disturbances in oxidative enzyme activity, and the presence of abnormal protein aggregates and vacuoles in some muscle fibers. Ultrastructural analysis showed inclusions composed of thin filaments and interspersed granular densities. DNA sequencing analysis detected a novel 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the FLNC gene. The patient's father, sister, brother, three paternal aunts, one paternal uncle, and the uncle's son also had slowly progressive muscle weakness, and thus, we detected an autosomal dominant inheritance pattern of the disorder. CONCLUSIONS: A novel heterogeneous 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the Ig-like domain 7 of the FLNC gene was found to cause filamin C-related MFM. This deletion in the FLNC gene causes protein aggregation, abnormalities in muscle structure, and impairment in muscle fiber function, which leads to muscle weakness.


Assuntos
Filaminas/genética , Miopatias Congênitas Estruturais/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Éxons/genética , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Deleção de Sequência/genética
18.
Gene ; 659: 160-167, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29551499

RESUMO

Recent achievements in the genetic diagnosis of Dilated Cardiomyopathy (DCM) have disclosed rare variants in numerous genes encoding different types of myocardial proteins. However, the causative gene underlying the pathogenesis of about 60% of familial cases with DCM has not been identified. One novel gene introduced in 2016 for cardiac-restricted DCM is FLNC. In this study, we applied Whole Exome Sequencing (WES) and bioinformatics-based methods to a member of an extended non-consanguineous family with DCM history accompanied with fatal arrhythmia in at least four consecutive generations. We found a novel splice-site mutation in FLNC gene (c.2389+1G>A) which cosegregated with all symptomatic individuals in the family. Computational prediction software tools as well as RT-PCR method were used to evaluate the impact of the FLNC splice site mutation. This substitution leads to exon 15th donor-site disruption and exon skipping, which would result in a premature stop codon three aminocids downstream of the mutation site. The aberrantly mRNA transcript can induce nonsense-mediated mRNA decay. Although carrier individuals show remarkable variable expression regarding the severity of DCM as well as the disease age of onset, a highly penetrant fatal arrhythmia was found to be shared between them. We strongly suggest that the involvement of FLNC gene, due to haploinsufficiency, should be considered in familial cases with DCM, especially if accompanied with arrhythmia and increased incidence of sudden cardiac death.


Assuntos
Processamento Alternativo , Cardiomiopatia Dilatada/genética , Filaminas/genética , Sequenciamento Completo do Exoma/métodos , Adulto , Família , Feminino , Predisposição Genética para Doença , Haploinsuficiência , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Mutação , Degradação do RNAm Mediada por Códon sem Sentido
19.
RNA ; 24(6): 828-840, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29592874

RESUMO

Recognition of dsRNA molecules activates the MDA5-MAVS pathway and plays a critical role in stimulating type-I interferon responses in psoriasis. However, the source of the dsRNA accumulation in psoriatic keratinocytes remains largely unknown. A-to-I RNA editing is a common co- or post-transcriptional modification that diversifies adenosine in dsRNA, and leads to unwinding of dsRNA structures. Thus, impaired RNA editing activity can result in an increased load of endogenous dsRNAs. Here we provide a transcriptome-wide analysis of RNA editing across dozens of psoriasis patients, and we demonstrate a global editing reduction in psoriatic lesions. In addition to the global alteration, we also detect editing changes in functional recoding sites located in the IGFBP7, COPA, and FLNA genes. Accretion of dsRNA activates autoimmune responses, and therefore the results presented here, linking for the first time an autoimmune disease to reduction in global editing level, are relevant to a wide range of autoimmune diseases.


Assuntos
Adenosina/genética , Inosina/genética , Queratinócitos/metabolismo , Psoríase/genética , Edição de RNA , RNA de Cadeia Dupla , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Células Cultivadas , Fator de Crescimento do Tecido Conjuntivo/genética , ATPases Transportadoras de Cobre/genética , Proteínas de Escherichia coli/genética , Feminino , Filaminas/genética , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Queratinócitos/citologia , Queratinócitos/imunologia , Masculino , Pessoa de Meia-Idade , Psoríase/imunologia , Psoríase/patologia , Adulto Jovem
20.
Brain Dev ; 40(6): 489-492, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29449050

RESUMO

INTRODUCTION: Filamin A (FLNA) is located in Xq28, and encodes the actin binding protein, filamin A. A mutation in FLNA is the most common cause of periventricular nodular heterotopia (PVNH), but a clear phenotype-genotype correlation has not been established. Indeed, some patients with a FLNA mutation have recently been shown to additionally have Ehlers-Danlos-like collagenopathy or macrothrombocytopenia. In an attempt to establish a clearer correlation between clinical symptoms and genotype, we have investigated a phenotype that involves thrombocytopenia in a patient with a truncation of the FLNA gene. CASE REPORT: We present the case of a 4-year-old girl who, at birth, showed a ventral hernia. At 2 months of age, she was diagnosed with patent ductus arteriosus (PDA) and aortic valve regurgitation. At 11 months, she underwent ligation of the PDA. She was also diagnosed with diaphragmatic eventration by a preoperative test. At 19 months, motor developmental delay was noted, and brain MRI revealed bilateral PVNH with mega cisterna magna. Presently, there is no evidence of epilepsy, intellectual disability or motor developmental delay. She has chronic, mild thrombocytopenia, and a platelet count that transiently decreases after viral infection. Dilation of the ascending aorta is progressing gradually. Genetic testing revealed a de novo nonsense heterozygous mutation in FLNA (NM_001456.3: c.1621G > T; p.Glu541Ter). Immunofluorescence staining of a peripheral blood smear showed a lack of filamin A expression in 21.1% of her platelets. These filamin A-negative platelets were slightly larger than her normal platelets. CONCLUSION: Our data suggests immunofluorescence staining of peripheral blood smears is a convenient diagnostic approach to identify patients with a FLNA mutation, which will facilitate further investigation of the correlation between FLNA mutations and patient phenotype.


Assuntos
Síndrome de Ehlers-Danlos/genética , Filaminas/genética , Heterotopia Nodular Periventricular/genética , Trombocitopenia/genética , Pré-Escolar , Diagnóstico Diferencial , Síndrome de Ehlers-Danlos/sangue , Síndrome de Ehlers-Danlos/diagnóstico por imagem , Feminino , Humanos , Mutação , Heterotopia Nodular Periventricular/sangue , Heterotopia Nodular Periventricular/diagnóstico por imagem , Fenótipo , Trombocitopenia/sangue , Trombocitopenia/diagnóstico por imagem
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