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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 961-964, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598936

RESUMO

OBJECTIVE: To analyze the clinical phenotype of a Chinese pedigree affected with Tuberous sclerosis complex (TSC) and explore pathogenic mutations of TSC1 and TSC2 gene. METHODS: Unique clinical phenotypes,the results of imaging, examination of the proband and special family history, collectively, made the constellation of features of TSC. Genomic DNA was obtained from six affected and eight unaffected members of the family and potential mutations of the TSC1 and TSC2 genes were detected by PCR-amplification of the exons and exon-intron boundaries and direct sequencing. A total of 150 normal unrelated individuals were used as controls. RESULTS: Genetic analysis documented the presence of a heterozygous mutation, c.1781_1782delTG (p.Val594GlyfsX11), in the exon 15 of TSC1 gene within all the patients of the family. This mutation was not observed in the eight unaffected family members or in the 150 unrelated control subjects from the same population , or the Human Gene Mutation Database (HGMD) and had completely co-segregated with the disease phenotype in the family. CONCLUSION: The c.1781_1782delTG mutation of TSC1 gene may be responsible for the tuberous sclerosis complex in this family. The data presented in the present study are of significance to clinicians, as well as genetic counselors, and may provide new clues for molecular diagnosis of this disease..


Assuntos
Proteína 1 do Complexo Esclerose Tuberosa/genética , Esclerose Tuberosa/genética , Análise Mutacional de DNA , Humanos , Mutação , Linhagem , Proteína 2 do Complexo Esclerose Tuberosa
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 1019-1021, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598950

RESUMO

OBJECTIVE: To identify pathogenic mutation of TSC1 and TSC2 genes in a patient with long-time misdiagnosis of epilepsy. METHODS: Peripheral blood samples and clinical data of the patient and her 2 parents were collected. Potential mutation of TSC1 and TSC2 genes were detected by direct sequencing. RESULTS: The patient had frequent episodes of epilepsy in addition with Shagreen patches for 10 years. A frame-shifting mutation c.2509_2512delAACA was detected in exon 20 of the TSC1 gene. This same mutation was not found in her unaffected parents. CONCLUSION: The recurrent frame-shifting mutation c.2509_2512delAACA (p.Asn837ValfsX11) of the TSC1 gene probably underlies the disease in this patient.


Assuntos
Epilepsia/diagnóstico , Epilepsia/genética , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética , Erros de Diagnóstico , Feminino , Mutação da Fase de Leitura , Humanos , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética
3.
Orv Hetil ; 160(21): 835-838, 2019 May.
Artigo em Húngaro | MEDLINE | ID: mdl-31104500

RESUMO

The advances in molecular genetic methods has lead to the discovery of the genetic alterations that underlie the etiology of most diseases previously held to be idiopathic. Targeted genetic examination of a pediatric male patient showing a normal intellect, an extended area of skin hypopigmentation, and suffering from generalized epilepsy displaying a switch in epilepsy syndrome during the course of the disease towards a neurocutaneous syndrome was unsuccessful. Whole-exome sequencing identified a heterozygous missense mutation in a potassium chloride cotransporter gene, which together with the phenotype underscores the diagnosis of an epilepsy syndrome known in the literature as idiopathic generalized epilepsy type 14. Orv Hetil. 2019; 160(21): 835-838.


Assuntos
Epilepsia Generalizada/etiologia , Canais Iônicos/genética , Mutação de Sentido Incorreto , Simportadores/genética , Criança , Humanos , Masculino , Mutação , Fenótipo , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Sequenciamento Completo do Exoma
4.
Brain Nerve ; 71(4): 374-379, 2019 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-30988224

RESUMO

Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disorders that is characterized by the systemic hamartomas, along with epilepsy, cognitive impairment and hypopigmented macules. It is caused by genetic mutations in either TSC1 or TSC2 gene which encodes hamartin and tuberin, respectively. As the hamartin-tuberin-complex downregulates the mechanistic/mammalian target of the rapamycin complex1 (mTORC1), dysfunction in either hamartin or tuberin induces the constitutive activation of mTORC1. In fact, almost all the symptoms in TSC are derived from the activation of mTORC1. Therefore, mTORC1 inhibitors improves all the symptoms, including skin lesions and neural symptoms. Among the many symptoms, skin lesions appear earlier than renal or pulmonary lesions and are more specific than neuronal symptoms. Therefore, skin lesions are useful for the diagnosis of TSC. This chapter focuses on the features of skin lesions and mechanistic their potential role in differential diagnosis and therapy including the therapeutic use of mTORC1 inhibitors.


Assuntos
Pele/patologia , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/patologia , Diagnóstico Diferencial , Epilepsia/patologia , Hamartoma/patologia , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Esclerose Tuberosa/tratamento farmacológico , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética
5.
Adv Genet ; 103: 91-118, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30904097

RESUMO

Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic condition caused by a mutation in either the TSC1 or TSC2 gene. Phenotypically, this leads to aberrant cell growth and the formation of benign tumors called hamartomas in multiple organs. Understanding the mechanisms of pathology that are caused through the presence of disease causing mutations is a real hurdle for many rare genetic disorders; a limiting factor that restricts knowledge of the disease and any hope of a future cure. Through the discovery of the TSC1 and TSC2 genes and the signaling pathways responsible for the pathology of TSC, a new drug target called mechanistic target of rapamycin complex 1 (mTORC1) was discovered. Rapamycin, an mTORC1 inhibitor, is now the only pharmacological therapy approved for the treatment of TSC. This chapter summarizes the success story of TSC and explores the future possibilities of finding a cure.


Assuntos
Esclerose Tuberosa/tratamento farmacológico , Esclerose Tuberosa/genética , Feminino , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Terapia de Alvo Molecular , Mutação , Transdução de Sinais , Sirolimo/uso terapêutico , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética
6.
Orphanet J Rare Dis ; 14(1): 72, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30922357

RESUMO

Endostatin is a naturally occurring collagen fragment with anti-angiogenic properties. We investigated the association between serum endostatin levels and DLCO in a cohort of patients with lymphangioleiomyomatosis (LAM). Associations of endostatin levels to clinical features of LAM were explored using logistic regression models. Endostatin levels were associated with DLCO and were higher in subjects with TSC-associated LAM compared to sporadic LAM. These data suggest that endostatin could be a predictive biomarker of decline in DLCO and that germline mutational inactivation of the TSC1 or TSC2 gene is associated with higher endostatin levels. These findings could offer novel insights into the pathogenesis of LAM.


Assuntos
Biomarcadores/sangue , Endostatinas/sangue , Linfangioleiomiomatose/sangue , Linfangioleiomiomatose/fisiopatologia , Adulto , Estudos de Coortes , Endostatinas/genética , Feminino , Inativação Gênica , Mutação em Linhagem Germinativa , Humanos , Linfangioleiomiomatose/complicações , Linfangioleiomiomatose/genética , Pessoa de Meia-Idade , Esclerose Tuberosa/complicações , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética
7.
Transl Psychiatry ; 9(1): 50, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30705255

RESUMO

The molecular signature underlying autism spectrum disorder remains largely unknown. This study identifies differential expression of mTOR and MAPK pathways in patients affected by mild and severe idiopathic autism. A total of 55 subjects were enrolled, of which 22 were typically developing individuals and 33 were patients aged between 3 and 11 years, with autism spectrum disorder. A detailed history, including physical examination, developmental evaluation, mental health history and autism diagnostic observation schedule were performed for each patient. Components of the mTOR and MAPK signalling pathways were analysed from peripheral blood at the protein level. Patients were then stratified according to their clinical phenotypes, and the molecular profiling was analysed in relation to the degree of autism severity. In this cohort of patients, we identified increased activity of mTOR and the MAPK pathways, key regulators of synaptogenesis and protein synthesis. Specifically, rpS6, p-eIF4E, TSC1 and p-MNK1 expression discriminated patients according to their clinical diagnosis, suggesting that components of protein synthesis signalling pathways might constitute a molecular signature of clinical severity in autism spectrum disorder.


Assuntos
Transtorno do Espectro Autista/genética , Sistema de Sinalização das MAP Quinases/genética , Neurogênese/genética , Serina-Treonina Quinases TOR/genética , Criança , Pré-Escolar , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Transporte Nucleocitoplasmático/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética
8.
PLoS One ; 14(2): e0212370, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30794603

RESUMO

Multifocal micronodular pneumocyte hyperplasia (MMPH) is a rare pulmonary disease, generally manifesting as a tuberous sclerosis complex (TSC), characterised by multiple, small ground-glass nodular shadows on chest computed tomography (CT). Histological examination typically reveals multicentric, well-demarcated, nodular type II pneumocystic growth. Herein, we describe three cases of this rare pulmonary disease occurring within one family. Using reverse transcription polymerase chain reaction (RT-PCR) and direct DNA sequencing, we identified a novel germline mutation, a point mutation in TSC1 intron 5, which yielded a splice variant and loss of function of TSC1. Furthermore, immunohistochemical staining indicated the expression of phospho-p70S6K and phospho-4E-BP1, suggesting that TSC1 function was impaired by the novel gene mutation in MMPH cells.


Assuntos
Processamento Alternativo , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Hiperplasia/genética , Pneumopatias/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Esclerose Tuberosa/genética , Adulto , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Sequência de Bases , Feminino , Humanos , Hiperplasia/patologia , Perda de Heterozigosidade , Pneumopatias/patologia , Masculino , Pessoa de Meia-Idade , Linhagem , Prognóstico , Esclerose Tuberosa/patologia
9.
Am J Pathol ; 189(1): 132-146, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30553437

RESUMO

Cartilage oligomeric matrix protein (COMP) is a large, multifunctional extracellular protein that, when mutated, is retained in the rough endoplasmic reticulum (ER). This retention elicits ER stress, inflammation, and oxidative stress, resulting in dysfunction and death of growth plate chondrocytes. While identifying the cellular pathologic mechanisms underlying the murine mutant (MT)-COMP model of pseudoachondroplasia, increased midline-1 (MID1) expression and mammalian target of rapamycin complex 1 (mTORC1) signaling was found. This novel role for MID1/mTORC1 signaling was investigated since treatments shown to repress the pathology also reduced Mid1/mTORC1. Although ER stress-inducing drugs or tumor necrosis factor α (TNFα) in rat chondrosarcoma cells increased Mid1, oxidative stress did not, establishing that ER stress- or TNFα-driven inflammation alone is sufficient to elevate MID1 expression. Since MID1 ubiquitinates protein phosphatase 2A (PP2A), a negative regulator of mTORC1, PP2A was evaluated in MT-COMP growth plate chondrocytes. PP2A was decreased, indicating de-repression of mTORC1 signaling. Rapamycin treatment in MT-COMP mice reduced mTORC1 signaling and intracellular retention of COMP, and increased proliferation, but did not change inflammatory markers IL-16 and eosinophil peroxidase. Lastly, mRNA from tuberous sclerosis-1/2-null mice brain tissue exhibiting ER stress had increased Mid1 expression, confirming the relationship between ER stress and MID1/mTORC1 signaling. These findings suggest a mechanistic link between ER stress and MID1/mTORC1 signaling that has implications extending to other conditions involving ER stress.


Assuntos
Acondroplasia , Proteína de Matriz Oligomérica de Cartilagem , Sistemas de Liberação de Medicamentos , Alvo Mecanístico do Complexo 1 de Rapamicina , Acondroplasia/tratamento farmacológico , Acondroplasia/genética , Acondroplasia/patologia , Animais , Biomarcadores/metabolismo , Proteína de Matriz Oligomérica de Cartilagem/genética , Proteína de Matriz Oligomérica de Cartilagem/metabolismo , Linhagem Celular Tumoral , Condrócitos/metabolismo , Condrócitos/patologia , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/genética , Retículo Endoplasmático Rugoso/genética , Retículo Endoplasmático Rugoso/metabolismo , Retículo Endoplasmático Rugoso/patologia , Peroxidase de Eosinófilo/genética , Peroxidase de Eosinófilo/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-16/genética , Interleucina-16/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Transgênicos , Mutação/genética , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Proteínas/genética , Proteínas/metabolismo , Ratos , Transdução de Sinais/genética , Sirolimo/farmacologia , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
11.
Cell Physiol Biochem ; 50(5): 1804-1814, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30396185

RESUMO

BACKGROUND/AIMS: MiR-19b has been reported to be involved in several malignancies, but its role in multiple myeloma (MM) is still unknown. The objective of this study was to explore the biological mechanism of miR-19b in the progression of MM. METHODS: First, we performed real-time polymerase chain reaction (PCR) and Western blot to study the expression of miR-19b, tuberous sclerosis 1 (TSC1), and caspase-3 in different groups. MTT assay was performed to explore the effect of miR-19b on survival and apoptosis of cancer stem cells (CSCs). Computation analysis and luciferase assay were utilized to confirm the interaction between miR-19b and TSC1. RESULTS: A total of 38 participants comprising 20 subjects with MM and 18 healthy subjects as normal controls were enrolled in our study. Real-time PCR showed dramatic upregulation of miR-19b, but TSC1 was evidently suppressed in the MM group. MiR-19b overexpression substantially promoted clonogenicity and cell viability, and further inhibited apoptosis of CSCs in vitro. Furthermore, miR-19b overexpression downregulated the expression of caspase-3, which induced apoptosis. Using in silico analysis, we identified that TSC1 might be a direct downstream target of miR-19b, and this was further confirmed by luciferase assay showing that miR-19b apparently reduced the luciferase activity of wild-type TSC1 3´-UTR, but not that of mutant TSC1 3´-UTR. There was also evident decrease in TSC1 mRNA and protein in CSCs following introduction of miR-19b. Interestingly, reintroduction of TSC1 abolished the miR-19b-induced proliferation promotion and apoptosis inhibition in CSCs. CONCLUSION: These findings collectively suggest that miR-19b promotes cell survival and suppresses apoptosis of MM CSCs via targeting TSC1 directly, indicating that miR-19b may serve as a potential and novel therapeutic target of MM based on miRNA expression.


Assuntos
Proliferação de Células , MicroRNAs/metabolismo , Mieloma Múltiplo/patologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regiões 3' não Traduzidas , Antagomirs/metabolismo , Apoptose , Sequência de Bases , Estudos de Casos e Controles , Caspase 3/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Mieloma Múltiplo/genética , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Alinhamento de Sequência , Proteína 1 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/genética
12.
Emerg Microbes Infect ; 7(1): 138, 2018 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-30087333

RESUMO

The latent reservoir of HIV-1 presents a major barrier to viral eradication. The mechanism of the establishment and maintenance of the latent viral reservoir is not yet fully understood, which hinders the development of effective curative strategies. In this study, we identified two inhibitory genes, TSC1 and DEPDC5, that maintained HIV-1 latency by suppressing the mTORC1 pathway. We first adapted a genome-wide CRISPR screening approach to identify host factors required for HIV latency in a T-cell-based latency model and discovered two inhibitory genes, TSC1 and DEPDC5, which are potentially involved in HIV-1 latency. Knockout of either TSC1 or DEPDC5 led to enhanced HIV-1 reactivation in both a T-cell line (C11) and a monocyte cell line (U1), and this enhancement could be antagonized by the mTORC1 inhibitor rapamycin. Further evaluation of the mechanism revealed that TSC1 suppresses AKT-mTORC1-S6 via downregulation of Rheb, whereas DEPDC5 inhibits AKT-mTORC1-S6 through RagA. Overall, both TSC1 and DEPDC5 negatively regulate the AKT-mTORC1 pathway, and thus their agonists could be used in the development of new therapeutic approaches for activating HIV-1 latency.


Assuntos
Infecções por HIV/metabolismo , HIV-1/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Latência Viral , Linhagem Celular , Infecções por HIV/enzimologia , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , Interações Hospedeiro-Patógeno , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo , Proteínas Repressoras/genética , Transdução de Sinais , Linfócitos T/metabolismo , Linfócitos T/virologia , Proteína 1 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Ativação Viral
13.
J Clin Pathol ; 71(10): 936-943, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29960980

RESUMO

AIM: We examined the genetic alterations in a mother and son with multiple eosinophilic chromophobe renal cell carcinomas (chRCCs) showing no other features. METHODS: Germline DNA and bilateral renal cell carcinoma DNA were genetically analysed by whole-exome sequencing. Candidate gene alterations in the first patient's germline were investigated in her child's germline and the chRCCs. RESULTS: We detected several germline gene alterations in the mother. Among the identified alterations, TSC1 and mitochondrial DNA mutations were also confirmed in her son. Regarding somatic alterations in bilateral chRCCs, no common candidate gene alteration was found. CONCLUSION: To the best of our knowledge, this is the first report of whole-exome sequencing revealing bilateral eosinophilic chRCCs associated with tuberous sclerosis complex in a family case without classical phenotype. These results suggest that germline TSC1 and mitochondrial DNA gene mutations may be involved in the development of chRCCs in some cases.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Proteínas Supressoras de Tumor/genética , Adulto , Carcinoma de Células Renais/patologia , DNA Mitocondrial/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Linhagem , Proteína 1 do Complexo Esclerose Tuberosa
14.
J Genet ; 97(2): 419-427, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29932062

RESUMO

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of hamartomas localized in various tissues which can occur in the skin, brain, kidney and other organs. TSC is caused by mutations in the TSC1 and TSC2 genes. Here we report the results from the first molecular testing of 16 Bulgarian patients and one Romanian patient in whom we found six novel mutations: four in the TSC22 gene, of which one is nonsense, two frame shift and one large deletion of 16 exons; and two in the TSC1 gene, one nonsense and other frame shift. In addition, we detected 10 previously reported mutations; some of which are described only once in the literature. Our data is similar to the previous studies with exception of the larger number of TSC1 mutations than that reported in the literature data. In total, 40% (4/10) of the mutation in the TSC2 gene are located in the GTPase-activating protein domain, while 50% (3/6) are in the TSC1 gene and clustered in exon 15. All the cases represent the typical clinical symptoms and meet the clinical criteria for TSC diagnosis. In 35% of our cases the family history was positive. Our results add novel findings in the genetic heterogeneity and pathogenesis of TSC. The genetic heterogeneity might correlate to the clinical variability among the TSC-affected families, which makes the genetic counselling a real challenge.


Assuntos
Predisposição Genética para Doença/genética , Mutação , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Sequência de Bases , Bulgária , Análise Mutacional de DNA , Testes Genéticos , Humanos , Romênia , Esclerose Tuberosa/diagnóstico , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa
15.
Proc Natl Acad Sci U S A ; 115(23): 5998-6003, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29784808

RESUMO

Nephrogenesis concludes by the 36th week of gestation in humans and by the third day of postnatal life in mice. Extending the nephrogenic period may reduce the onset of adult renal and cardiovascular disease associated with low nephron numbers. We conditionally deleted either Mtor or Tsc1 (coding for hamartin, an inhibitor of Mtor) in renal progenitor cells. Loss of one Mtor allele caused a reduction in nephron numbers; complete deletion led to severe paucity of glomeruli in the kidney resulting in early death after birth. By contrast, loss of one Tsc1 allele from renal progenitors resulted in a 25% increase in nephron endowment with no adverse effects. Increased progenitor engraftment rates ex vivo relative to controls correlated with prolonged nephrogenesis through the fourth postnatal day. Complete loss of both Tsc1 alleles in renal progenitors led to a lethal tubular lesion. The hamartin phenotypes are not dependent on the inhibitory effect of TSC on the Mtor complex but are dependent on Raptor.


Assuntos
Néfrons , Organogênese/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Néfrons/química , Néfrons/citologia , Néfrons/crescimento & desenvolvimento , Néfrons/fisiologia , Serina-Treonina Quinases TOR/genética , Proteína 1 do Complexo Esclerose Tuberosa
16.
J Dermatol ; 45(7): 867-870, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29740858

RESUMO

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease characterized by hamartomas in multiple organ systems. This study was performed in one familial and two sporadic cases with TSC. Two novel mutations (c.1884_1887delAAAG and c.5266A>G) and two previously reported mutations (c.4258_4261delTCAG and c.1960G>C) were identified by direct DNA sequencing. Of the four mutations, c.1884_1887delAAAG and c.1960G>C were found in a family and identified in the same allele by TA cloning sequencing. However, c.1960G>C was reported to be non-pathogenic. Furthermore, correlations between genotypes and phenotypes of Chinese Han patients since 2014 were performed by paired χ2 -tests in our published work review, which has not been reported. The results showed that patients with TSC2 mutations had a higher frequency of mental retardation and there were no significant differences of seizures and skin lesions with TSC1 mutations. Genetically, they had a higher frequency of familial inheritance.


Assuntos
Deficiência Intelectual/genética , Convulsões/genética , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Encéfalo/diagnóstico por imagem , Criança , Análise Mutacional de DNA , Eletroencefalografia , Éxons/genética , Feminino , Genótipo , Humanos , Deficiência Intelectual/diagnóstico , Mutação , Fenótipo , Convulsões/diagnóstico , Pele/patologia , Tomografia Computadorizada por Raios X , Esclerose Tuberosa/diagnóstico por imagem , Esclerose Tuberosa/patologia , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa
17.
Acta Dermatovenerol Croat ; 26(1): 73-74, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29782307

RESUMO

Dear Editor, Tuberous sclerosis (TS) is an autosomal dominant multisystem disease, which occurs due to genetically determined hyperplasia of ectodermal and mesodermal cells. Clinical manifestations present on the skin and in the nervous system, kidneys, heart, and other organs. Recent studies estimate the incidence of TS at 1/6000 to 1/10,000 live births, and a prevalence in the general population of approximately 1 in 20,000 (1). There are two different genetic loci responsible for TS: 9q34 (TSC1-hamartin) and 16p13.3 (TSC2-tuberin) (2). Cutaneous manifestations occur in about 96% of patients (3). Neurological disorders occur in 50% of patients in the form of seizures and motor and psychomotor symptomatology (4). A 19-year-old male patient was hospitalized for clinical and diagnostic evaluation in February 2016 year in Clinic for Nephrology, Clinical Center of Montenegro, Podgorica, Montenegro. Polycystic kidney changes were verified by ultrasound when the patient was three years old, with the presence of several calcified nodules in lateral ventricles and supraventricularly in the brain as well as the existence of several hypopigmented maculae on the skin. During the last hospitalization in February 2016, the following tests were performed: cranial magnet resonance imaging (MRI) findings showed the existence of visible changes in the signal in the form of ectopic tuber tissue in the region of the cortex and subcortical white matter of the brain, but without neurological and psychomotor abnormalities; ultrasound of the urinary tract showed that both kidneys were enlarged with multiple cysts, with dominant cysts at the lower pole of the right kidney with a size of 55 mm and at the upper pole of the left kidney, approximately 40 mm. Reduced functional capacity of kidneys was found on dynamic scintigraphy, slightly more in the left kidney (41%) compared with the right (59%). Electroencephalography, X-ray of the lungs and heart, and echocardiography were also performed, but without any pathological findings. Dermatological examination found numerous fibroma up to 0.5 cm in diameter, the largest located nasolabially, periorally, and on the chin skin (Figure 1) at the age of seven, whereas a fibroma and several white maculae were present from birth on the skin of the forehead. They were now also present on the skin of the trunk and on the upper and lower extremities (Figure 2), accompanied by surrounding minor changes in the form of confetti-like maculae. A subungual fibroma was present on the third finger of the right hand. Collagen nevus (shagreen patch) (5), i.e. a subepidermal fibrosis as a mildly elevated, palm-sized area is also characteristic of TS, which is described in literature, in most cases in the lumbosacral region. In our case, such a fibrosis about 3 cm in diameter, and with the consistency of an orange peel, was discovered on the right shoulder. Subungual fibromas (Koenen tumors) (6), which can develop in adolescence, were present in our patient on the third finger of the right hand. The diagnosis of TS was established based on genetic testing, physical examination, ultrasound-verified polycystic kidney disease and reduced global renal functions, intracranial MRI, many hypomelanotic changes, and angiofibromas found with dermatological examination (7). There is no specific therapeutic approach for TS, and the treatment is symptomatic. Angiofibromas of the skin can be removed by dermabrasion or laser. Recent data show a good therapeutic effect of applying 0.1% rapamycin (8), which leads to a reduction of angiofibromas in patients with TS. On dermatological follow up after five weeks of application of tacrolimus, angiofibromas of the face were in regression. Some studies suggest the simultaneous topical applications of both of those drugs (9). In adolescents and adults of reproductive age, genetic counseling is recommended (10).


Assuntos
Angiofibroma/patologia , Imagem Multimodal , Neoplasias Cutâneas/patologia , Esclerose Tuberosa/patologia , Proteínas Supressoras de Tumor/genética , Angiofibroma/genética , Angiofibroma/terapia , Biópsia por Agulha , Terapia Combinada , Eletroencefalografia/métodos , Humanos , Imuno-Histoquímica , Terapia a Laser/métodos , Imagem por Ressonância Magnética/métodos , Masculino , Prognóstico , Índice de Gravidade de Doença , Sirolimo/administração & dosagem , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Esclerose Tuberosa/genética , Esclerose Tuberosa/terapia , Proteína 1 do Complexo Esclerose Tuberosa , Ultrassonografia Doppler/métodos , Adulto Jovem
18.
J Clin Neurosci ; 54: 39-44, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29803333

RESUMO

Tuberous scleroses complex (TSC) is a rare neurocutaneous syndrome and has autosomal dominant inheritance. However, larger family with TSC is very rare. Here, we report the first five generations family with TSC from China, and localize the pathogenic gene. A boy with TSC and epilepsy underwent preoperative evaluation and epileptic surgery. His TSC family history was gotten, and the clinical data of a Chinese family with TSC were collected in 2016. Complete exons sequencing was performed in the proband and his parents, and whole exons sequence of TSC was performed in the other family members. The family showed autosomal dominant inheritance, and it was the largest reported family with TSC. In this pedigree, there were 14 patients in 5 generations, but only 1 case with epilepsy in them. All of examined patients had TSC 1 gene exon 15 c.1846delG p.A616Pfs*13 mutation. In conclusion, TSC patients with TSC 1 deletion presented mild neurological symptom and rendered larger family.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/genética , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Criança , Pré-Escolar , Éxons , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Proteína 1 do Complexo Esclerose Tuberosa
19.
Medicine (Baltimore) ; 97(15): e0112, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29642139

RESUMO

Although fetal cardiac rhabdomyoma can be the initial finding in patients with tuberous sclerosis complex (TSC), the challenges of precise genetic diagnosis of TSC can now be potentially overcome by new whole or targeted genomic sequencing. The goals of this study were to investigate the correlation between suspected cardiac rhabdomyoma and TSC to provide the information for a prenatal diagnosis of TSC and to validate the TSC genotype in this cohort of fetuses with suspected prenatal cardiac rhabdomyoma.We retrospectively analyzed 10,728 fetal echocardiograms from January 2013 to March 2016 in our institution. A total of 32 fetuses were suspected of having cardiac rhabdomyomas. Among them, 15 subjects met the inclusion criteria and provided written consent. Samples from fetuses (n = 13 after terminations) and newborns (n = 2) were available for targeted genomic sequencing of the exons and introns of the TSC1 and TSC2 genes and the adjacent 10 base pairs and for validated studies using Sanger sequencing.Among the 15 subjects with suspected cardiac rhabdomyoma and TSC genomic sequencing data, 7 subjects were familial and 8 subjects were sporadic cases. Fetal echocardiography showed a single tumor in 2 fetuses and multiple tumors in 13 fetuses. Gene sequencing analysis showed no mutation of the TSC1 or TSC2 gene in 2 subjects with a single tumor but positive mutations in all 13 subjects with multiple tumors. Among the latter, 5 mutations were "pathogenic" and have been previously reported (4 familial and 1 sporadic). Six new mutations were "likely pathogenic" and had not been previously reported (3 familial and 3 sporadic); 1 was of "uncertain significance" (sporadic), and 1 was suspected of being "likely benign" (sporadic).Prenatal suspected cardiac rhabdomyoma detected by fetal echocardiography should raise the suspicion of TSC. In fetuses with multiple tumors, especially the familial cases, genomic sequencing has a high yield of detecting TSC-causing genes. Patient history, prenatal fetal echocardiography, and targeted genomic sequencing may facilitate screening for, diagnosis of, and counseling for TSC.


Assuntos
Neoplasias Cardíacas , Diagnóstico Pré-Natal/métodos , Rabdomioma , Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Ecocardiografia/métodos , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/genética , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/etiologia , Neoplasias Cardíacas/patologia , Humanos , Recém-Nascido , Imagem por Ressonância Magnética/métodos , Masculino , Mutação , Gravidez , Estudos Retrospectivos , Rabdomioma/diagnóstico , Rabdomioma/etiologia , Rabdomioma/patologia , Análise de Sequência de DNA/métodos , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa
20.
Biochem Biophys Res Commun ; 498(1): 234-239, 2018 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-29501742

RESUMO

Diabetes and obesity are commonly associated with Alzheimer's disease (AD). Accumulating evidence show that insulin signaling defects are protentional upstream driver of AD. However, the mechanism by which diabetes and insulin signaling defects contribute to AD remains unknown. Here we show that Fat mass and obesity-associated protein (FTO) is involved the insulin defects-associated AD. Defective insulin signaling in diabetes and obesity in human and mice activated Fto in the brain tissues. Lentivirus-mediated knockdown of Fto reduced the phosphorylation of Tau protein whereas overexpression of FTO promoted the level of phosphorylated Tau in neurons. Mechanism study demonstrated that FTO activated the phosphorylation of Tau in a mTOR-dependent manner because FTO activated mTOR and its downstream signaling and rapamycin blocked FTO-mediated phosphorylation of Tau. FTO promoted the activation of mTOR by increasing the mRNA level of TSC1 but not TSC2, the upstream inhibitor of mTOR. Finally, we found that conditional knockout of Fto in the neurons reduced the cognitive deficits in 3xTg AD mice. Collectively, our evidence demonstrated that FTO is critically involved in insulin defects-related AD.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas tau/metabolismo , Envelhecimento/patologia , Dioxigenase FTO Dependente de alfa-Cetoglutarato/deficiência , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Masculino , Camundongos Knockout , Obesidade/metabolismo , Obesidade/patologia , Fosforilação , Proteína 1 do Complexo Esclerose Tuberosa
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