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1.
Medicine (Baltimore) ; 98(35): e16909, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464924

RESUMO

RATIONALE: Congenital hepatic fibrosis (CHF) is an autosomal recessive disease characterized by periportal fibrosis, portal hypertension, and renal cystic disease. Essentially, CHF is a variant of fibrocystic disorder in which liver and kidney are commonly affected. Other frequently associated conditions include Caroli syndrome and polycystic kidney disease. CHF is also a known accompaniment in an array of inherited disorders with multiorgan involvement. PATIENT CONCERNS: The 20-year-old male patient with declining vision (14 years duration), intermittent gingival bleeding (7 years duration), and abdominal distension (5 years duration), presented with exacerbation of these symptoms during the prior 2 months. The patient had been previously diagnosed with retinal macular degeneration, idiopathic thrombocytopenic purpura, and hepatosplenomegaly. DIAGNOSES: Liver biopsy showed disordered hepatic acini and fibrous parenchymal banding, indicative of CHF. INTERVENTIONS: After the treatment of diuresis and liver protectants, the clinical symptoms of the patients were improved. We subsequently recommend chromosomal analysis, although the family refused. OUTCOMES: Three months after discharge, the patient was followed up by telephone. The patient had obvious abdominal distension and we advised that he should be admitted again. But the family refused. LESSONS: CHF is an AR disease resulting in portal hypertension and often associated with renal malformations. CHF is also linked to a number of other disorders, many of which are ciliopathies. Because the clinical manifestations of CHF are nonspecific or lacking, its diagnosis is problematic, relying largely on liver biopsy. Once CHF is identified, physicians are obligated to investigate other organ systems, particularly a search for neuromuscular, retina or renal involvement. This case underscores the value of radiologic imaging, pathologic examination, and genetic testing in successfully diagnosing a rare disease.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Cirrose Hepática/diagnóstico , Fígado/patologia , Biópsia , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/patologia , Hemorragia Gengival/etiologia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Degeneração Macular , Masculino , Recusa do Paciente ao Tratamento , Adulto Jovem
3.
Med Oncol ; 36(9): 74, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332543

RESUMO

Hereditary renal cell carcinoma syndromes (HRCCS) are characterized by the presence of pathogenic germline variants that predispose patients to renal cell carcinomas as well as additional extra-renal manifestations. The importance of identifying HRCCS patients cannot be overemphasized, as patients and their families can begin surveillance for syndrome-associated manifestations once identified. The present study is a retrospective clinical and morphologic review of 60 hereditary renal tumors from 30 HRCCS patients treated at our institution with either Von Hippel-Lindau disease (VHL), Birt-Hogg-Dubé syndrome (BHD), tuberous sclerosis complex (TSC), hereditary leiomyomatosis and renal cell cancer syndrome, or succinate dehydrogenase (SDH) deficiency syndrome. Hereditary renal cell carcinoma syndromes kidney tumors often demonstrate specific morphologic features, characteristic background changes in renal parenchyma, and extra-renal manifestations, which, when recognized by the pathologist, can trigger genetic testing referral for specific familial cancer syndromes. Our study demonstrates the majority of tumors were consistent with the anticipated clinicopathologic profile of renal tumors found within HRCCS patients, although we found some unique characteristics within this cohort including a case of clear cell papillary renal cell carcinoma within a VHL patient, and a unique renal tumor with tubulopapillary features present in a patient with a germline SDHD mutation. Additionally, although the literature reports the presence of epithelioid angiomyolipoma (AML) as a common occurrence in TSC patients, our cohort of 3 patients with AMLs demonstrated only classic features. The findings we describe facilitate pathologist-based recognition of HRCCS and can prompt genetic evaluation for relevant patients.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Síndromes Neoplásicas Hereditárias/patologia , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/terapia , Criança , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Doenças Genéticas Inatas/terapia , Humanos , Rim/patologia , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Tecido Parenquimatoso/patologia , Estudos Retrospectivos , Succinato Desidrogenase/deficiência , Succinato Desidrogenase/genética , Centros de Atenção Terciária , Adulto Jovem
4.
Medicine (Baltimore) ; 98(20): e15600, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096464

RESUMO

INTRODUCTION: Congenital hepatic fibrosis (CHF) is a rare autosomal recessive disease derived from biliary dysgenesis secondary to ductal plate malformation and is often accompanied by renal cysts or increased renal echogenicity. PATIENT CONCERNS: A 25-year-old woman was admitted to our hospital with splenomegaly and hepatic cirrhosis of a 3-month duration and fever accompanied by abdominal pain for 3 days. The second patient was a 25-year-old male referred to our hospital with hepatomegaly and splenomegaly of 6-year duration who had experienced fever for 3 months and abdominal distension for 1 week. Both 25-year-old patients were found to have CHF with polycystic kidney disease. DIAGNOSIS: Radiological imaging, including computed tomography (CT), magnetic resonance imaging (MRI), and sonography, revealed hepatic fibrosis, portal hypertension, splenomegaly, ascites, bile duct malformation, polycystic kidneys, and CHF. For the first patient, a liver biopsy confirmed the pathological features of CHF, and genetic testing revealed three heterozygous missense mutations, which were classified as "undetermined" in the public Wilson's disease/ATP7B and ADPKD/PKD1 databases. INTERVENTIONS: The first patient had undergone a splenectomy for anemia 2 months previously. Because there is no radical cure for CHF, and due to economic reasons, neither patient received liver transplantation. Therefore, we administered only anti-fibrotic supportive treatment for symptoms. OUTCOMES: Both patients were discharged after their symptoms improved, and both survived for 2 years of follow-up. CONCLUSION: These cases highlight the value of radiological imaging, pathological examination, and genetic evaluation for the diagnosis of CHF. When an individual with unexplained cirrhosis presents with bile duct dilation and malformation as well as polycystic kidneys, the possibility of CHF should be considered. For individuals found to have polycystic kidneys at a young age, the results of liver function tests and imaging examinations including Fibroscan imaging should be continuously and dynamically monitored to enable early diagnosis of CHF.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Cirrose Hepática/diagnóstico , Adulto , Doenças dos Ductos Biliares/etiologia , Feminino , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/diagnóstico por imagem , Doenças Genéticas Inatas/patologia , Humanos , Hipertensão Portal/etiologia , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Masculino , Doenças Renais Policísticas/etiologia , Esplenomegalia/etiologia
5.
Eur J Med Genet ; 62(8): 103647, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31026593

RESUMO

Preimplantation genetic testing (PGT) has been successfully applied to reduce the risk of miscarriage, improve IVF success rates, and prevent inheritance of monogenic disease and unbalanced translocations. The present study provides the first method capable of simultaneous testing of aneuploidy (PGT-A), structural rearrangements (PGT-SR), and monogenic (PGT-M) disorders using a single platform. Using positive controls to establish performance characteristics, accuracies of 97 to >99% for each type of testing were observed. In addition, this study expands PGT to include predicting the risk of polygenic disorders (PGT-P) for the first time. Performance was established for two common diseases, hypothyroidism and type 1 diabetes, based upon availability of positive control samples from commercially available repositories. Data from the UK Biobank, eMERGE, and T1DBASE were used to establish and validate SNP-based predictors of each disease (7,311 SNPs for hypothyroidism and 82 for type 1 diabetes). Area under the curve of disease status prediction from genotypes alone were 0.71 for hypothyroidism and 0.68 for type 1 diabetes. The availability of expanded PGT to evaluate the risk of polygenic disorders in the preimplantation embryo has the potential to lower the prevalence of common genetic disease in humans.


Assuntos
Aborto Espontâneo/genética , Cromossomos/genética , Doenças Genéticas Inatas/genética , Diagnóstico Pré-Implantação , Aborto Espontâneo/fisiopatologia , Aneuploidia , Biópsia , Blastocisto/metabolismo , Feminino , Doenças Genéticas Inatas/patologia , Variação Estrutural do Genoma/genética , Genótipo , Humanos , Cariótipo , Herança Multifatorial/genética , Gravidez
6.
Cells ; 8(4)2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925787

RESUMO

Mitochondrial fatty acid oxidation (FAO) and respiratory chain (RC) defects form a large group of inherited monogenic disorders sharing many common clinical and pathophysiological features, including disruption of mitochondrial bioenergetics, but also, for example, oxidative stress and accumulation of noxious metabolites. Interestingly, several transcription factors or co-activators exert transcriptional control on both FAO and RC genes, and can be activated by small molecules, opening to possibly common therapeutic approaches for FAO and RC deficiencies. Here, we review recent data on the potential of various drugs or small molecules targeting pivotal metabolic regulators: peroxisome proliferator activated receptors (PPARs), sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK), and protein kinase A (PKA)) or interacting with reactive oxygen species (ROS) signaling, to alleviate or to correct inborn FAO or RC deficiencies in cellular or animal models. The possible molecular mechanisms involved, in particular the contribution of mitochondrial biogenesis, are discussed. Applications of these pharmacological approaches as a function of genotype/phenotype are also addressed, which clearly orient toward personalized therapy. Finally, we propose that beyond the identification of individual candidate drugs/molecules, future pharmacological approaches should consider their combination, which could produce additive or synergistic effects that may further enhance their therapeutic potential.


Assuntos
Doenças Genéticas Inatas/tratamento farmacológico , Doenças Genéticas Inatas/patologia , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/patologia , Transdução de Sinais , Animais , Transporte de Elétrons , Metabolismo Energético , Humanos , Oxirredução
7.
BMC Endocr Disord ; 19(1): 25, 2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782163

RESUMO

BACKGROUND: Immune checkpoint inhibitors including nivolumab, an anti-programmed cell death protein 1 antibody, are recently developed cancer immunotherapy agents. Immune checkpoint inhibitors are known to cause autoimmune-related side effects including endocrine dysfunctions. However, there are few reports on late-onset isolated adrenocorticotropic hormone (ACTH) deficiency caused by nivolumab. CASE PRESENTATION: The patient was a 72-year-old female. When she was 64 years old, she was diagnosed with malignant melanoma of the left thigh accompanied by left inguinal lymph node metastases, and she received several courses of chemotherapy for malignant melanoma followed by the resection of these lesions. At 71 years of age, multiple metastases were found and treatment with nivolumab 2 mg/kg every 3 weeks was initiated. Six months later, replacement with levothyroxine was started because of hypothyroidism following mild transient thyrotoxicosis. Eleven months after the beginning of nivolumab, the treatment was discontinued because of tumor expansion. Four months after the discontinuation of nivolumab, general malaise and appetite loss worsened, and 2 months later, hyponatremia (Na; 120-127 mEq/L) and hypoglycemia (fasting plasma glucose; 62 mg/dL) appeared. Her ACTH and cortisol levels were extremely low (ACTH; 9.6 pg/mL, cortisol; undetectable). Challenge tests for anterior pituitary hormones showed that responses of ACTH and cortisol secretion to corticotropin-releasing hormone were disappeared, although responses of other anterior pituitary hormones were preserved. Thus, she was diagnosed with isolated ACTH deficiency. Her symptoms were improved after treatment with hydrocortisone. CONCLUSIONS: The present report showed a case of late-onset isolated ACTH deficiency accompanied by hyponatremia, which was diagnosed 6 months after the discontinuation of nivolumab. The effects of nivolumab last for a long time and the side effects of nivolumab can also appear several months after discontinuation of the drug. Repeated monitoring of serum sodium levels may be a beneficial strategy to find the unexpected development of adrenal insufficiency even after discontinuation of nivolumab.


Assuntos
Hormônio Adrenocorticotrópico/deficiência , Antineoplásicos Imunológicos/efeitos adversos , Doenças do Sistema Endócrino/induzido quimicamente , Doenças Genéticas Inatas/induzido quimicamente , Hipoglicemia/induzido quimicamente , Melanoma/tratamento farmacológico , Nivolumabe/efeitos adversos , Idade de Início , Idoso , Doenças do Sistema Endócrino/patologia , Feminino , Doenças Genéticas Inatas/patologia , Humanos , Hipoglicemia/patologia , Prognóstico
8.
Nat Rev Genet ; 20(7): 377-388, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30737492

RESUMO

The derivation of induced pluripotent stem cells (iPSCs) over a decade ago sparked widespread enthusiasm for the development of new models of human disease, enhanced platforms for drug discovery and more widespread use of autologous cell-based therapy. Early studies using directed differentiation of iPSCs frequently uncovered cell-level phenotypes in monogenic diseases, but translation to tissue-level and organ-level diseases has required development of more complex, 3D, multicellular systems. Organoids and human-rodent chimaeras more accurately mirror the diverse cellular ecosystems of complex tissues and are being applied to iPSC disease models to recapitulate the pathobiology of a broad spectrum of human maladies, including infectious diseases, genetic disorders and cancer.


Assuntos
Doenças Transmissíveis/terapia , Doenças Genéticas Inatas/terapia , Células-Tronco Pluripotentes Induzidas/citologia , Modelos Biológicos , Neoplasias/terapia , Engenharia Tecidual/métodos , Animais , Diferenciação Celular , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Quimera/genética , Quimera/imunologia , Doenças Transmissíveis/genética , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/patologia , Descoberta de Drogas/métodos , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/patologia , Terapia Genética/métodos , Humanos , Células-Tronco Pluripotentes Induzidas/imunologia , Células-Tronco Pluripotentes Induzidas/transplante , Modelos Animais , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Organoides/citologia , Organoides/efeitos dos fármacos , Organoides/imunologia , Transplante de Tecidos/métodos , Transplante Heterólogo
9.
Stem Cell Res ; 35: 101398, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30772683

RESUMO

Fibroblasts of a patient with Infantile Liver Failure Syndrome 2 (OMIM #616483) due to a homozygous missense variant in the neuroblastoma amplified sequence gene (NBAS; c.[2708T>G]; c.[2708T>G]/p.[Leu903Arg]; p.[Leu903Arg]) were reprogrammed to iPSCs using the Cytotune®-iPS 2.0 Sendai Reprogramming Kit (Invitrogen) delivering the reprogramming factors Oct3/4, Sox2, c-Myc and Klf4. Cells showed a normal karyotype. Pluripotency of DHMCi004-A was proven using immunohistochemistry, RT-PCR analysis, flow cytometry and differentiation into all three germ layers using the STEMdiff™ Trilineage Differentiation Kit (Stemcell Technologies). DHMCi004-A represents the first iPS-based cell model system to elucidate the pathomechanism underlying this disease.


Assuntos
Linhagem Celular , Doenças Genéticas Inatas , Células-Tronco Pluripotentes Induzidas , Falência Hepática , Mutação de Sentido Incorreto , Proteínas de Neoplasias , Pré-Escolar , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Falência Hepática/genética , Falência Hepática/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Síndrome
10.
PLoS One ; 14(2): e0212198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30794581

RESUMO

INTRODUCTION: The system of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (cas) is a new technology that allows easier manipulation of the genome. Its potential to edit genes opened a new door in treatment development for incurable neurological monogenic diseases (NMGDs). The aim of this systematic review was to summarise the findings on the current development of CRISPR-cas for therapeutic purposes in the most frequent NMGDs and provide critical assessment. METHODS AND DATA ACQUISITION: We searched the MEDLINE and EMBASE databases, looking for original studies on the use of CRISPR-cas to edit pathogenic variants in models of the most frequent NMGDs, until end of 2017. We included all the studies that met the following criteria: 1. Peer-reviewed study report with explicitly described experimental designs; 2. In vitro, ex vivo, or in vivo study using human or other animal biological systems (including cells, tissues, organs, organisms); 3. focusing on CRISPR as the gene-editing method of choice; and 5. featured at least one NMGD. RESULTS: We obtained 404 papers from MEDLINE and 513 from EMBASE. After removing the duplicates, we screened 490 papers by title and abstract and assessed them for eligibility. After reading 50 full-text papers, we finally selected 42 for the review. DISCUSSION: Here we give a systematic summary on the preclinical development of CRISPR-cas for therapeutic purposes in NMGDs. Furthermore, we address the clinical interpretability of the findings, giving a comprehensive overview of the current state of the art. Duchenne's muscular dystrophy (DMD) paves the way forward, with 26 out of 42 studies reporting different strategies on DMD gene editing in different models of the disease. Most of the strategies aimed for permanent exon skipping by deletion with CRISPR-cas. Successful silencing of the mHTT gene with CRISPR-cas led to successful reversal of the neurotoxic effects in the striatum of mouse models of Huntington's disease. Many other strategies have been explored, including epigenetic regulation of gene expression, in cellular and animal models of: myotonic dystrophy, Fraxile X syndrome, ataxias, and other less frequent dystrophies. Still, before even considering the clinical application of CRISPR-cas, three major bottlenecks need to be addressed: efficacy, safety, and delivery of the systems. This requires a collaborative approach in the research community, while having ethical considerations in mind.


Assuntos
Sistemas CRISPR-Cas , Expansão das Repetições de DNA , Edição de Genes/métodos , Técnicas de Transferência de Genes , Doenças Genéticas Inatas , Doenças Neuromusculares , Animais , Modelos Animais de Doenças , Edição de Genes/tendências , Inativação Gênica , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Doenças Genéticas Inatas/terapia , Humanos , MEDLINE , Camundongos , Doenças Neuromusculares/genética , Doenças Neuromusculares/patologia , Doenças Neuromusculares/terapia
11.
J Neurol ; 266(3): 680-690, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30666435

RESUMO

OBJECTIVE: Hereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and considered quite rare. Respiratory insufficiency is an early symptom. A collection of families and patients with muscle disease suggestive of HMERF was clinically and genetically studied. METHODS: Altogether 12 new families with 19 affected patients and diverse nationalities were studied. Most of the patients were investigated using targeted next-generation sequencing; Sanger sequencing was applied in some of the patients and available family members. Histological data and muscle MRI findings were evaluated. RESULTS: Three families had several family members studied while the rest were single patients. Most patients had distal and proximal muscle weakness together with respiratory insufficiency. Five heterozygous TTN A-band mutations were identified of which two were novel. Also with the novel mutations the muscle pathology and imaging findings were compatible with the previous reports of HMERF. CONCLUSIONS: Our collection of 12 new families expands mutational spectrum with two new mutations identified. HMERF is not that rare and can be found worldwide, but maybe underdiagnosed. Diagnostic process seems to be complex as this study shows with mostly single patients without clear dominant family history.


Assuntos
Conectina/genética , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/fisiopatologia , Doenças Musculares/genética , Doenças Musculares/fisiopatologia , Insuficiência Respiratória/genética , Insuficiência Respiratória/fisiopatologia , Adulto , Idade de Início , Feminino , Doenças Genéticas Inatas/diagnóstico por imagem , Doenças Genéticas Inatas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Doenças Musculares/diagnóstico por imagem , Doenças Musculares/patologia , Mutação , Linhagem , Insuficiência Respiratória/diagnóstico por imagem , Insuficiência Respiratória/patologia , Adulto Jovem
12.
J Clin Invest ; 129(2): 442-451, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30614813

RESUMO

The field of hereditary kidney cancer has begun to mature following the identification of several germline syndromes that define genetic and molecular features of this cancer. Molecular defects within these hereditary syndromes demonstrate consistent deficits in angiogenesis and metabolic signaling, largely driven by altered hypoxia signaling. The classical mutation, loss of function of the von Hippel-Lindau (VHL) tumor suppressor, provides a human pathogenesis model for critical aspects of pseudohypoxia. These features are mimicked in a less common hereditary renal tumor syndrome, known as hereditary leiomyomatosis and renal cell carcinoma. Here, we review renal tumor angiogenesis and metabolism from a HIF-centric perspective, considering alterations in the hypoxic landscape, and molecular deviations resulting from high levels of HIF family members. Mutations underlying HIF deregulation drive multifactorial aberrations in angiogenic signals and metabolism. The mechanisms by which these defects drive tumor growth are still emerging. However, the distinctive patterns of angiogenesis and glycolysis-/glutamine-dependent bioenergetics provide insight into the cellular environment of these cancers. The result is a scenario permissive for aggressive tumorigenesis especially within the proximal renal tubule. These features of tumorigenesis have been highly actionable in kidney cancer treatments, and will likely continue as central tenets of kidney cancer therapeutics.


Assuntos
Carcinoma de Células Renais , Doenças Genéticas Inatas , Neoplasias Renais , Leiomiomatose , Síndromes Neoplásicas Hereditárias , Neovascularização Patológica , Proteína Supressora de Tumor Von Hippel-Lindau , Hipóxia Celular/genética , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Doenças Genéticas Inatas/terapia , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Leiomiomatose/genética , Leiomiomatose/metabolismo , Leiomiomatose/patologia , Leiomiomatose/terapia , Modelos Biológicos , Mutação , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/metabolismo , Síndromes Neoplásicas Hereditárias/patologia , Síndromes Neoplásicas Hereditárias/terapia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neovascularização Patológica/terapia , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
13.
J Allergy Clin Immunol ; 143(1): 292-304.e8, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29775636

RESUMO

BACKGROUND: Mutations in tetratricopeptide repeat domain 7A (TTC7A) and its mouse orthologue, Ttc7, result in a multisystemic disease, mostly affecting the epithelial barriers and immune system. Despite successful hematopoietic stem cell transplantation, ongoing progression of gastrointestinal manifestations can be life-threatening in TTC7A-deficient patients. OBJECTIVE: We sought to identify whether TTC7A mutations dysregulate epithelial cells only or whether a cell-intrinsic defect in lymphocytes or other cells contributes to disease manifestations. METHODS: Ttc7-mutated (Ttc7fsn/fsn) mice were crossed to generate double-mutant (Rag2-/-Ttc7fsn/fsn) and triple-mutant (Rag2-/-IL2rg-/-Ttc7fsn/fsn) mice. These models, together with bone marrow chimeras, were used to explore the role of adaptive and innate lymphocytes in the flaky skin phenotype. The effect of the Ttc7fsn/fsn mutation on stromal cells was tested in a xenograft model in conjunction with transcriptomic analysis of Ttc7fsn/fsn fibroblasts. RESULTS: We observed that the severity of epithelial hyperproliferation was accentuated by lymphocytes, whereas the phenotype was not induced by transfer of Ttc7-mutated hematopoietic cells. Furthermore, mice completely lacking the lymphocytic compartment were not protected from epithelial hyperproliferation. Ttc7-mutated mouse fibroblasts expressed increased transcript levels of insulin-like growth factor 1 (Igf1) and the antimicrobial protein regenerating islet-derived protein 3γ (Reg3γ). In a xenograft model Ttc7-mutated fibroblasts markedly increased epithelial proliferation of keratinocytes. Thus Ttc7-mutated fibroblasts were identified as potent instigators of epithelial hyperproliferation. CONCLUSION: Our results reveal a previously unsuspected fundamental cell-extrinsic role of Ttc7. We have identified potential candidates for molecularly targeted treatment strategies that will need to be evaluated in future preclinical studies.


Assuntos
Proliferação de Células , Dermatite/imunologia , Células Epiteliais/imunologia , Fibroblastos/imunologia , Doenças Genéticas Inatas/imunologia , Linfócitos/imunologia , Mutação , Proteínas/imunologia , Animais , Células 3T3 BALB , Dermatite/genética , Dermatite/patologia , Células Epiteliais/patologia , Fibroblastos/patologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Humanos , Linfócitos/patologia , Camundongos , Camundongos Knockout , Proteínas/genética
14.
J Allergy Clin Immunol ; 143(1): 276-291.e6, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29800648

RESUMO

BACKGROUND: Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphoinositide 3-kinase (PI3K), result in hyperactivation of the PI3K-AKT-mechanistic target of rapamycin pathway and underlie a novel inborn error of immunity. Affected subjects exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or cytomegalovirus infection, and increased incidence of B-cell lymphoproliferation, lymphoma, or both. Mechanisms underlying disease pathogenesis remain unknown. OBJECTIVE: Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in patients with PIK3CD GOF mutations, identify key molecules required for cell-mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this and other EBV-opathies. METHODS: We studied the consequences of PIK3CD GOF mutations on the generation, differentiation, and function of CD8+ T cells and natural killer (NK) cells, which are implicated in host defense against infection with herpesviruses, including EBV. RESULTS: PIK3CD GOF total and EBV-specific CD8+ T cells were skewed toward an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion and increased susceptibility to reactivation-induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF mutations. NK cells in patients with PIK3CD GOF mutations also exhibited perturbed expression of differentiation-associated molecules. Both CD8+ T and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, programmed death ligand 1/2, and CD70. CONCLUSIONS: PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8+ T and NK cells. These defects might contribute to clinical features of affected subjects, such as impaired immunity to herpesviruses and tumor surveillance.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Classe I de Fosfatidilinositol 3-Quinases , Infecções por Vírus Epstein-Barr , Mutação com Ganho de Função , Doenças Genéticas Inatas/imunologia , Herpesvirus Humano 4/imunologia , Células Matadoras Naturais/imunologia , Adolescente , Adulto , Idoso , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/genética , Senescência Celular/genética , Senescência Celular/imunologia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/patologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Humanos , Vigilância Imunológica/genética , Células Matadoras Naturais/patologia , Masculino , Pessoa de Meia-Idade
15.
Genet Med ; 21(1): 124-132, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29875419

RESUMO

PURPOSE: We aimed to assess the definition of actionability of secondary findings in childhood, using a screening framework. METHODS: For 31 disorders on the American College of Medical Genetics and Genomics SF v.2.0 list, World Health Organization screening criteria were applied to assess actionability in childhood. RESULTS: The age of onset was variable. We categorized disorders based on the proportion of cases that presented in childhood: rare (n = 6), fewer than half the cases (n = 9), the majority of cases (n = 12), or unclear (n = 4). The age at initiation of intervention was based on the youngest age of onset reported, not evidence of the benefit of early intervention. For 15 disorders, guidelines were supported by a moderate quality of evidence for at least one recommendation. Only tuberous sclerosis complex had recommendations based on high-quality evidence. All others were based on evidence of low or very low quality. CONCLUSION: We propose that actionability in childhood should be based on the proportion of cases that manifest in childhood and the quality of the evidence supporting intervention recommendations. Ideally, disclosure in childhood would be limited to disorders for which a majority of cases present in childhood and for which interventions are supported by evidence of at least moderate quality (i.e., multiple endocrine neoplasia type 2, retinoblastoma, tuberous sclerosis complex, Marfan syndrome, and Wilson's disease).


Assuntos
Doenças Genéticas Inatas/genética , Testes Genéticos , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala , Adolescente , Criança , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/patologia , Genômica , Degeneração Hepatolenticular/diagnóstico , Degeneração Hepatolenticular/epidemiologia , Degeneração Hepatolenticular/genética , Humanos , Masculino , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/epidemiologia , Síndrome de Marfan/genética , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2a/epidemiologia , Neoplasia Endócrina Múltipla Tipo 2a/genética , Retinoblastoma/diagnóstico , Retinoblastoma/epidemiologia , Retinoblastoma/genética , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/epidemiologia , Esclerose Tuberosa/genética
17.
Genet Med ; 21(1): 207-212, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29961769

RESUMO

PURPOSE: Genomic studies have demonstrated the necessity of ethnicity-specific population data to ascertain variant pathogenicity for disease diagnosis and treatment. This study examined the carrier prevalence of treatable inherited disorders (TIDs), where early diagnosis of at-risk offspring can significantly improve clinical outcomes. METHODS: Existing exome/ genome sequencing data of 831 Singaporeans were aggregated and examined for disease causing variants in 104 genes associated with 80 TIDs. RESULTS: Among the 831 Singaporean participants, genomic variant filtering and analysis identified 1 in 18 individuals (6%) to be carriers amongst one of 13 TIDs. Citrin deficiency and Wilson disease had the highest carrier frequency of 1 in 41, and 1 in 103 individuals, respectively. The pathogenic variants associated with citrin deficiency were 24 times more prevalent in our local cohorts when compared to Western cohorts. CONCLUSION: This study demonstrates the value of a population specific genomic database to determine true disease prevalence and has enabled the discovery of carrier frequencies of treatable genetic conditions specific to South East Asian populations, which are currently underestimated in existing data sources. This study framework can be adapted to other population groups and expanded to multiple genetic conditions to inform health policies directing precision medicine.


Assuntos
Exoma/genética , Triagem de Portadores Genéticos , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Ásia , Grupos Étnicos , Frequência do Gene , Doenças Genéticas Inatas/classificação , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/patologia , Variação Genética , Genética Populacional , Humanos , Masculino , Metagenômica , Mutação/genética , Medicina de Precisão
18.
Mol Cell Biochem ; 453(1-2): 157-161, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30155659

RESUMO

Endocardial endothelial cells constitute a barrier between the circulating blood and ventricular cardiomyocytes. Although recently our group demonstrated the importance of this type of endothelial cells in excitation-secretion coupling, there is no information on whether this type of cells contributes to cardiac pathologies such as cardiac hypertrophy. Using the well-known model of human hypertrophy and heart failure, the UM-X7.1 hereditary cardiomyopathic hamster, our results showed that during the phase of necrosis and in the absence of cardiac hypertrophy, isolated endocardial endothelial cells underwent a significant increase in cell volume compared to cells isolated from age-matched normal hamsters. This increase of the volume of endocardial endothelial cells persisted during the development of cardiac hypertrophy in the hereditary cardiomyopathic hamster. These results demonstrate for the first time, that endocardial endothelial hypertrophy precedes the development of hypertrophy in hereditary cardiomyopathy and may, via its released factors, contribute to the development of cardiac hypertrophy. These results demonstrate the importance of endocardial endothelial cells in cardiac diseases such as hypertrophy. This type of cells constitutes a new target for understanding hypertrophy and heart failure.


Assuntos
Cardiomegalia/metabolismo , Endocárdio/metabolismo , Células Endoteliais/metabolismo , Doenças Genéticas Inatas/metabolismo , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Cricetinae , Modelos Animais de Doenças , Endocárdio/patologia , Células Endoteliais/patologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia
19.
Mitochondrion ; 46: 321-325, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30205178

RESUMO

Genetic contributing factors to non-syndromic hearing loss (NSHL) are remarkably diverse spanning over autosomal to X-linked to mitochondrial inheritance patterns. Facing a quite unconventional pedigree, here we report implementation of whole exome sequencing (WES) to uncover mitochondrial pathogenic variant in a six-generation Iranian family with four cases affected with hereditary NSHL of variable severity. As a result, heteroplasmic transition of A to G at position 1555 of MT-RNR1 gene was identified in all affected individuals co-existing with nuclear c.28G > T (p.A10S) variant in the TRMU gene, only in some patients. The reliability of WES to infer nuclear as well as mitochondrial variants in hearing loss were discussed.


Assuntos
Doenças Genéticas Inatas/genética , Perda Auditiva/genética , Mutação Puntual , RNA Mitocondrial/genética , RNA Ribossômico/genética , tRNA Metiltransferases/genética , Adulto , Feminino , Doenças Genéticas Inatas/patologia , Perda Auditiva/patologia , Humanos , Irã (Geográfico) , Proteínas Mitocondriais , Linhagem , Sequenciamento Completo do Exoma
20.
Genet Med ; 21(1): 114-123, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29895855

RESUMO

PURPOSE: We investigated the frequencies and characteristics of intragenic copy-number variants (CNVs) in a deep sampling of disease genes associated with monogenic disorders. METHODS: Subsets of 1507 genes were tested using next-generation sequencing to simultaneously detect sequence variants and CNVs in >143,000 individuals referred for genetic testing. We analyzed CNVs in gene panels for hereditary cancer syndromes and cardiovascular, neurological, or pediatric disorders. RESULTS: Our analysis identified 2844 intragenic CNVs in 384 clinically tested genes. CNVs were observed in 1.9% of the entire cohort but in a disproportionately high fraction (9.8%) of individuals with a clinically significant result. CNVs accounted for 4.7-35% of pathogenic variants, depending on clinical specialty. Distinct patterns existed among CNVs in terms of copy number, location, exons affected, clinical classification, and genes affected. Separately, analysis of de-identified data for 599 genes unrelated to the clinical phenotype yielded 4054 CNVs. Most of these CNVs were novel rare events, present as duplications, and enriched in genes associated with recessive disorders or lacking loss-of-function mutational mechanisms. CONCLUSION: Universal intragenic CNV analysis adds substantial clinical sensitivity to genetic testing. Clinically relevant CNVs have distinct properties that distinguish them from CNVs contributing to normal variation in human disease genes.


Assuntos
Variações do Número de Cópias de DNA/genética , Estudos de Associação Genética , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Hibridização Genômica Comparativa , Éxons/genética , Doenças Genéticas Inatas/patologia , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fenótipo
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