RESUMEN
Objective: To explore the mutation characteristics of pathogenic genes in children with congenital hypothyroidism (CH) in Fujian. Methods: The clinical data of 116 unrelated CH children diagnosed in Fujian Provincial Maternal and Child Health Hospital from January 2019 to September 2020 were retrospectively analyzed, including 50 females and 66 males, with an average age of (20±10) days at diagnosis. Targeted exome sequencing technology was used to detect the mutation frequency, type and distribution characteristics of 29 genes related to thyroxine synthesis or thyroid development. Results: Three hundred and fifty-one potential functional mutations were detected in 105 of 116 CH patients, with a detection rate of 90.5% (105/116). DUOX2 (66.4%, 77/116) was the most frequent mutated gene, followed by TG (23.3%, 27/116), DUOXA1 (23.3%, 27/116), and TPO (12.1%, 14/116), which were all involved in thyroid hormone synthesis. Among the 105 children with CH, 70 cases carried double allele mutation. Except for 3 cases of thyroid dysplasia related genes (2 cases of TSHR and 1 case of GLIS3), the rest were also related to thyroid hormone synthesis. The gene with the highest carrier rate was DUOX2 (68.8%, 59/70), followed by TG (8.6%, 6/70), TPO (4.3%, 3/70), DUOXA2 (1.4%, 1/70) and DUOXA1 (1.4%, 1/70). Conclusion: The main mutated genes in CH children in Fujian are the key genes involved in thyroid hormone synthesis, such as DUOX2, TG and TPO.
Asunto(s)
Hipotiroidismo Congénito , Femenino , Humanos , Recién Nacido , Masculino , Hipotiroidismo Congénito/genética , Hipotiroidismo Congénito/diagnóstico , Oxidasas Duales/genética , Mutación , Estudios Retrospectivos , Tiroxina/genéticaRESUMEN
OBJECTIVE: Neurogenic hypertension is a type of hypertension characterized by increased sympathetic activity. Vascular compression is one of the pathogenic mechanisms of neurogenic hypertension. The sample sizes of currently available studies on MVD in the treatment of hypertension are small, and the results are considerably different. Therefore, we conducted a meta-analysis of the previous literature to obtain the most realistic efficiency and analyzed the current situation of MVD as a treatment option of the vascular compression type of neurogenic hypertension. METHOD: We systematically searched and identified relevant studies published before July 2019 from PubMed and Embase. Six studies involving 162 participants were included into our final analysis. RESULT: The data showed that the effective rate of MVD was 70.1% (95% CI: 0.602-0.801). The most common offending vessel was PICA (29.9%), followed by VA/BA (23.9%) and VA/BA plus PICA (12.7%). Complications were mostly related to the VII, VIII, IX, and/or X cranial nerve dysfunction. CONCLUSION: MVD as a treatment option of the vascular compression type of neurogenic hypertension is effective and safe. In spite of this conclusion, more prospective studies are needed to confirm it. On the other hand, a diagnostic method with higher sensitivity and specificity is necessary.
Asunto(s)
Hipertensión , Cirugía para Descompresión Microvascular , Espasmo Hemifacial/cirugía , Humanos , Estudios Prospectivos , Resultado del Tratamiento , Neuralgia del Trigémino/cirugíaRESUMEN
Graves' disease (GD) is a complex autoimmune disorder in which genetic and environmental factors are both involved in the pathogenesis. Early-onset patients have a shorter exposure time to environmental factors and are, therefore, good models to help understand the genetic architecture of GD. Based on previous studies of early-onset GD, 11 single nucleotide polymorphisms (SNPs) and their related SNPs (R2 > .6), SNPs located within a ±1-Mb region of the FOXP3 gene, and 20 validated GD-risk SNPs were selected and screened for genotyping in 3735 GD and 4893 control patients to investigate whether early-onset GD is a subtype of GD with distinct susceptibility genes. Ultimately, we did not confirm the reported genetic markers of early-onset GD in our Chinese Han population but found that a GD-risk SNP located in the human leukocyte antigen class I region-rs4947296-was more strongly correlated with early-onset GD than non-early-onset GD. In addition, heterogeneity analysis of GD patients suggests that it may be more reasonable to define early-onset GD as an onset age ≤20 years.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Enfermedad de Graves/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Edad de Inicio , Alelos , Pueblo Asiatico/genética , China , Femenino , Factores de Transcripción Forkhead/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/etnología , Genotipo , Enfermedad de Graves/etnología , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) caused by MEN1 mutation is widely recognized. To date, 14 novel mutations were reported in Chinese and intronic mutations are getting more attention. AIM: To explore clinical features and MEN1 mutations in two Chinese families suffering from MEN1. METHODS: Nineteen individuals (10 males and 9 females) from two unrelated families with MEN1 were studied. Mutations of MEN1 were analyzed by direct sequencing of PCR products. In vitro splicing analysis was also performed with minigenes containing both wildtype and novel mutant fragments. Through the RNAstructure program, we analyzed the secondary structure of the wild type MEN1 pre-mRNA and then introduced T>G mutation at +2 donor splice site of intron 7. RESULTS: Clinical features of 3 patients in two families were described, and 5 individuals were proven to be carriers of MEN1 mutation without apparent symptoms. A novel splicing site mutation of the intron 7 (IVS7+2 TâG) was identified in the first family. In vitro analysis also verified this mutation caused the aberrant splicing of MEN1 mRNA. With the RNAstructure program, we could figure out that the global secondary structure as well as the number of stems and loops of pre-mRNA greatly changed after this mutation. The mutation c. 1227 C>A (C409X) was identified in another family, which also caused the truncation of menin. CONCLUSION: We reported a novel intronic mutation and a missense mutations in two Chinese families suffering from MEN1.
Asunto(s)
Neoplasia Endocrina Múltiple Tipo 1/genética , Mutación Missense , Proteínas Proto-Oncogénicas/genética , Adulto , Anciano de 80 o más Años , Pueblo Asiatico/genética , Secuencia de Bases , Niño , Preescolar , Femenino , Humanos , Lactante , Intrones/genética , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación Missense/fisiología , Conformación de Ácido Nucleico , Linaje , Precursores del ARN/química , Precursores del ARN/genéticaRESUMEN
Porokeratosis is a rare disorder of epidermal keratinization that is characterized by the presence of a border called the cornoid lamella. Disseminated superficial porokeratosis (DSP) is a subtype of porokeratosis, which is inherited as an autosomal trait. The first locus for DSP was localized to chromosome 18p11.3, but no causative gene has yet been identified. In this study, we recruited and analysed a large six-generation Chinese family with autosomal dominant DSP. The genome-wide screening identified a maximum two-point LOD score of 3.06 at θ = 0.00 with the microsatellite marker D12S78. Fine mapping and haplotype analysis defined a critical region of 38 Mb between D12S326 and D12S79 on chromosome 12q21.2-24.21, which is a probable second locus identified for DSP (DSP2). We sequenced 50 candidate genes in this region, but no causative mutation was found. This study provides a map location for isolation of a gene causing DSP.
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Cromosomas Humanos Par 12/genética , Poroqueratosis/genética , Adolescente , Adulto , Pueblo Asiatico/genética , Niño , Mapeo Cromosómico , Femenino , Ligamiento Genético , Marcadores Genéticos , Humanos , Masculino , Repeticiones de Microsatélite/genética , Adulto JovenRESUMEN
Aldosterone is considered as a new cardiovascular risk factor that plays an important role in metabolic syndrome; however, the underlying mechanism of these effects is not clear. Hypoadiponectinemia and elevated circulating concentration of plasminogen activator inhibitor-1 (PAI-1) are causally associated with obesity-related insulin resistance and cardiovascular disease. The aim of the present study is to investigate the effect of aldosterone on the production of adiponectin and PAI-1 in 3T3-L1 adipocytes. Northern and Western blot analyses revealed that aldosterone treatment inhibited adiponectin mRNA expression and secretion and simultaneously enhanced PAI-1 mRNA expression and secretion in a time- and dose-dependent manner. Rosiglitazone did not prevent aldosterone's effect on adiponectin or PAI-1 expression. In contrast, tumor necrosis factor (TNF)-α produced dramatic synergistic effects on adiponectin and PAI-1 expression when added together with aldosterone. Furthermore, the effects of aldosterone on adiponectin and PAI-1 expression appear to be mediated through glucocorticoid receptor (GR) but not mineralocorticoid receptor (MR). These results suggest that the effects of aldosterone on adiponectin and PAI-1 production are one of the underlying mechanisms linking it to insulin resistance, metabolic syndrome and cardiovascular disease.
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Adipocitos/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Aldosterona/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Ratones , Antagonistas de Receptores de Mineralocorticoides , PPAR gamma/agonistas , PPAR gamma/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Factores de TiempoRESUMEN
In addition to serving as a fat depot, adipose tissue is also considered as an important endocrine organ that synthesizes and secretes a number of factors. Leptin is an adipocyte-derived hormone that plays a vital role in energy balance. Expression of leptin is regulated by dietary status and hormones. In the present study, we report that galanin, an orexigenic peptide, inhibits leptin expression and secretion in rat adipose tissue and in 3T3-L1 adipocytes. Treatment with galanin (25 micro g/animal) induced approximately 46% down-regulation of leptin secretion at 15 min, followed by 40, 37 and 47% decreases in leptin secretion at 1, 2 and 4 h respectively. Although Northern blot analysis of adipose tissue from the same animals showed that leptin mRNA expression in adipose tissue was unaffected by galanin treatment for 2 h, galanin treatment for 4 h led to decline of leptin mRNA expression in a dose-dependent manner. Meanwhile, treating the rats with galanin had no effect on leptin mRNA expression in the hypothalamus. The inhibitory action of the galanin on leptin mRNA and protein levels was also observed in vitro. When incubated with 10 nM galanin for 48 h, leptin mRNA expression and protein secretion also decreased in 3T3-L1 adipocytes. On the other hand, galanin was found not only to express in rat adipose tissue, but also to increase about 8-fold after fasting. Based on these data, we speculate that increased galanin expression in rat adipose tissue after fasting may be involved in reducing leptin expression and secretion in fasting rats.
Asunto(s)
Tejido Adiposo/efectos de los fármacos , Galanina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Leptina/genética , Células 3T3-L1 , Tejido Adiposo/metabolismo , Animales , Secuencia de Bases , Northern Blotting , Western Blotting , Cartilla de ADN , Ayuno , Hibridación in Situ , Leptina/sangre , Leptina/metabolismo , Masculino , Ratones , Reacción en Cadena de la Polimerasa , Ratas , Ratas Sprague-Dawley , Receptores de Galanina/genética , Receptores de LeptinaRESUMEN
Insulinoma is a clinically common cause of organic hypoglycemia. The prominent characteristic of insulinoma is endogenous hyperinsulinism. Until now, the molecular biology of human insulinoma has been little understood. In this study, gene expression profiling of human insulinoma was established by expressed sequence tag (EST) sequencing and cDNA array. A total of 2063 clones were obtained, of these, 1589 clones were derived from EST sequencing, 975 clones were derived from cDNA array and 501 clones were shared by the two methods. G protein alpha-stimulating activity polypeptide (Gsalpha) and carboxypeptidase E (CPE) were the most highly expressed genes in human insulinoma, as derived by EST sequencing and cDNA array respectively. The genes involved in the protein/insulin secretion pathway were strongly expressed in human insulinoma tissue. Meanwhile, eight full-length cDNAs of novel genes were cloned and sequenced. The results demonstrated the molecular biology of human insulinoma tissue at the level of transcript abundance and validated the efficacy of EST sequencing combined with cDNA array in the construction of gene expression profiling. In conclusion, the predominance of the genes participating in the secretory pathway suggested that regulation of secretion might be a major mechanism by which insulin release is abnormally increased in patients with insulinomas. It was also concluded that overexpression of the Gsalpha gene played an important role in the pathogenesis of insulinoma.
Asunto(s)
Perfilación de la Expresión Génica , Insulina/metabolismo , Insulinoma/genética , Neoplasias Pancreáticas/genética , Clonación Molecular , Regulación Neoplásica de la Expresión Génica , Humanos , Secreción de Insulina , Insulinoma/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Pancreáticas/metabolismoRESUMEN
Pheochromocytoma is a chromaffin cell neoplasm that typically causes symptoms and signs of episodic catecholamine release. Pheochromocytoma can be divided into two types: familial and sporadic. The molecular mechanisms involved in familial pheochromocytoma have been unraveled, but the detailed molecular mechanism of sporadic pheochromocytoma remains unknown. The present study thus aimed at characterization of gene expression profiling of sporadic pheochromocytoma using expressed sequence tags (ESTs), and established a preliminary catalog of genes expressed in the tumor. In total, 4115 ESTs were generated from the tumor library. The gene expression profilings of the pheochromocytoma and the normal adrenal gland were compared, and 341 genes were identified to be significantly expressed differently between the two libraries. Interestingly, 16 known genes participating in cell division or apoptosis were notably differently expressed between the tumor and the normal adrenal gland. Twenty-four novel full-length cDNAs were cloned from the tumor library and five of them were significantly up-regulated in the tumor. Some of them may be involved in the tumorigenesis of pheochromocytoma. The sequence data of ESTs and novel full-length cDNAs described in this paper have been submitted to the GeneBank library.
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Neoplasias de las Glándulas Suprarrenales/genética , Feocromocitoma/genética , Neoplasias de las Glándulas Suprarrenales/metabolismo , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Clonación Molecular , ADN Complementario/química , ADN Complementario/genética , Etiquetas de Secuencia Expresada , Perfilación de la Expresión Génica , Biblioteca de Genes , Humanos , Masculino , Datos de Secuencia Molecular , Feocromocitoma/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Análisis de Secuencia de ADNRESUMEN
The primary neuroendocrine interface, hypothalamus and pituitary, together with adrenals, constitute the major axis responsible for the maintenance of homeostasis and the response to the perturbations in the environment. The gene expression profiling in the human hypothalamus-pituitary-adrenal axis was catalogued by generating a large amount of expressed sequence tags (ESTs), followed by bioinformatics analysis (http://www.chgc.sh.cn/ database). Totally, 25,973 sequences of good quality were obtained from 31,130 clones (83.4%) from cDNA libraries of the hypothalamus, pituitary, and adrenal glands. After eliminating 5,347 sequences corresponding to repetitive elements and mtDNA, 20,626 ESTs could be assembled into 9, 175 clusters (3,979, 3,074, and 4,116 clusters in hypothalamus, pituitary, and adrenal glands, respectively) when overlapping ESTs were integrated. Of these clusters, 2,777 (30.3%) corresponded to known genes, 4,165 (44.8%) to dbESTs, and 2,233 (24.3%) to novel ESTs. The gene expression profiles reflected well the functional characteristics of the three levels in the hypothalamus-pituitary-adrenal axis, because most of the 20 genes with highest expression showed statistical difference in terms of tissue distribution, including a group of tissue-specific functional markers. Meanwhile, some findings were made with regard to the physiology of the axis, and 200 full-length cDNAs of novel genes were cloned and sequenced. All of these data may contribute to the understanding of the neuroendocrine regulation of human life.