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1.
J Org Chem ; 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31475536

RESUMO

Three new monoterpenoid indole alkaloids (MIAs), hunterines A-C (1-3), were isolated from Hunteria zeylanica. Compound 1 possesses a unique skeleton with an unprecedented azabicyclo[4.3.1]decane ring system. Compounds 2 and 3 are a pair of epimeric vobasinyl-indole alkaloid heterodimers. Their structures including absolute configurations were established by spectroscopic analyses, X-ray diffraction, computational calculation, and modified Mosher's method. The plausible biogenetic pathways of 1-3 were also proposed. Alkaloid 1 showed moderate cytotoxic activity against HepG2 cell line.

2.
Clin Genet ; 96(3): 207-215, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31066047

RESUMO

Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous conditions. We launched a nationwide study to determine the frequency of CMD in the Chinese population and assess the status of diagnosis and disease management for CMD in China. Cases were chosen from databases in 34 tertiary academic hospitals from 29 first-level administrative divisions (provinces, municipalities, autonomous regions, and special administrative regions), and medical records were reviewed to confirm the diagnoses. The study included 409 patients, of those patients who consented to genetic testing (n = 340), mutations were identified in 286 of them. The most common forms identified were LAMA2-related CMD (36.4%), followed by COL6-related CMD (23.2%) and α-dystroglycanopathy (21.0%). The forms of CMD related to mutations in LMNA and SEPN1 were less frequent (12.5% and 2.4%, respectively). We also recorded a significant difference in the diagnostic capabilities and disease management of CMD, with this being relatively backward in research centers from less developed regions. We provide, for the first time, comprehensive epidemiologic information of CMD in a large cohort of Chinese people. To our knowledge, this is the largest sample size of its kind so far highlighting the prevalence of CMD in China.

3.
Diabetes ; 66(4): 935-947, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28130309

RESUMO

Some Shanghai Clinical Center f a role of Niemann-Pick type C1 (NPC1) for obesity traits. However, whether the loss-of-function mutations in NPC1 cause adiposity in humans remains unknown. We recruited 25 probands with rare autosomal-recessive Niemann-Pick type C (NP-C) disease and their parents in assessment of the effect of heterozygous NPC1 mutations on adiposity. We found that male NPC1+/- carriers had a significantly higher BMI than matched control subjects or the whole population-based control subjects. Consistently, male NPC1+/- mice had increased fat storage while eating a high-fat diet. We further conducted an in-depth assessment of rare variants in the NPC1 gene in young, severely obese subjects and lean control subjects and identified 17 rare nonsynonymous/frameshift variants in NPC1 (minor allele frequency <1%) that were significantly associated with an increased risk of obesity (3.40% vs. 0.73%, respectively, in obese patients and control subjects, P = 0.0008, odds ratio = 4.8, 95% CI 1.7-13.2), indicating that rare NPC1 variants were enriched in young, morbidly obese Chinese subjects. Importantly, participants carrying rare variants with severely damaged cholesterol-transporting ability had more fat accumulation than those with mild/no damage rare variants. In summary, rare loss-of-function NPC1 mutations were identified as being associated with human adiposity with a high penetrance, providing potential therapeutic interventions for obesity in addition to the role of NPC1 in the familial NP-C disease.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas de Transporte/genética , Dieta Hiperlipídica , Glicoproteínas de Membrana/genética , Obesidade Mórbida/genética , Proteínas/genética , Adulto , Animais , Estudos de Casos e Controles , China , Feminino , Mutação da Fase de Leitura , Frequência do Gene , Predisposição Genética para Doença , Variação Genética , Heterozigoto , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Obesidade/genética , Fenótipo , Adulto Jovem
4.
J Hum Genet ; 61(12): 1013-1020, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27439679

RESUMO

Mutations in the fukutin-related protein (FKRP) gene have been associated with dystroglycanopathies, which are common in Europe but rare in Asia. Our study aimed to retrospectively analyze and characterize the clinical, myopathological and genetic features of 12 Chinese patients with FKRP mutations. Three patients were diagnosed with congenital muscular dystrophy type 1C (MDC1C) and nine patients were diagnosed with limb girdle muscular dystrophy type 2I (LGMD2I). Three muscle biopsy specimens had dystrophic changes and reduced glycosylated α-dystroglycan staining, and two showed reduced expression of laminin α2. Two known and 13 novel mutations were identified in our single center cohort. Interestingly, the c.545A>G mutation was found in eight of the nine LGMD2I patients as a founder mutation and this founder mutation in Chinese patients differs from the one seen in European patients. Moreover, patients homozygous for the c.545A>G mutation were clinically asymptomatic, a less severe phenotype than in compound heterozygous patients with the c.545A>G mutation. The 13 novel mutations of FKRP significantly expanded the mutation spectrum of MDC1C and LGMD2I, and the different founder mutations indicate the ethnic difference in FKRP mutations.


Assuntos
Efeito Fundador , Estudos de Associação Genética , Mutação , Fenótipo , Proteínas/genética , Adolescente , Biópsia , Encéfalo/patologia , Criança , Pré-Escolar , Feminino , Genótipo , Haplótipos , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Músculo Esquelético/patologia , Distrofias Musculares/diagnóstico , Distrofias Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/genética
5.
Zhonghua Er Ke Za Zhi ; 53(10): 741-6, 2015 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-26758109

RESUMO

OBJECTIVE: To elucidate the usefulness of next generation sequencing for diagnosis of inherited myopathy, and to analyze the relevance between clinical phenotype and genotype in inherited myopathy. METHOD: Related genes were selected for SureSelect target enrichment system kit (Panel Version 1 and Panel Version 2). A total of 134 patients who were diagnosed as inherited myopathy clinically underwent next generation sequencing in Department of Pediatrics, Peking University First Hospital from January 2013 to June 2014. Clinical information and gene detection result of the patients were collected and analyzed. RESULT: Seventy-seven of 134 patients (89 males and 45 females, visiting ages from 6-month-old to 26-year-old, average visiting age was 6 years and 1 month) underwent next generation sequencing by Panel Version 1 in 2013, and 57 patients underwent next generation sequencing by Panel Version 2 in 2014. The gene detection revealed that 74 patients had pathogenic gene mutations, and the positive rate of genetic diagnosis was 55.22%. One patient was diagnosed as metabolic myopathy. Five patients were diagnosed as congenital myopathy; 68 were diagnosed as muscular dystrophy, including 22 with congenital muscular dystrophy 1A (MDC1A), 11 with Ullrich congenital muscular dystrophy (UCMD), 6 with Bethlem myopathy (BM), 12 with Duchenne muscular dystrophy (DMD) caused by point mutations in DMD gene, 5 with LMNA-related congenital muscular dystrophy (L-CMD), 1 with Emery-Dreifuss muscular dystrophy (EDMD), 7 with alpha-dystroglycanopathy (α-DG) patients, and 4 with limb-girdle muscular dystrophy (LGMD) patients. CONCLUSION: Next generation sequencing plays an important role in diagnosis of inherited myopathy. Clinical and biological information analysis was essential for screening pathogenic gene of inherited myopathy.


Assuntos
Análise Mutacional de DNA , Doenças Genéticas Inatas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Doenças Musculares/diagnóstico , Adolescente , Criança , Pré-Escolar , Contratura , Feminino , Doenças Genéticas Inatas/genética , Testes Genéticos , Genótipo , Humanos , Lactente , Masculino , Técnicas de Diagnóstico Molecular , Doenças Musculares/genética , Distrofias Musculares/congênito , Distrofia Muscular do Cíngulo dos Membros , Distrofia Muscular de Duchenne , Distrofia Muscular de Emery-Dreifuss , Mutação , Fenótipo , Esclerose , Síndrome de Walker-Warburg , Adulto Jovem
6.
Beijing Da Xue Xue Bao Yi Xue Ban ; 46(1): 130-7, 2014 Feb 18.
Artigo em Chinês | MEDLINE | ID: mdl-24535365

RESUMO

OBJECTIVE: To summarize the etiology and clinical characteristics of children with myopathic elevated creatine kinase (CK) levels. The degrees of elevated CK as well as lactic dehydrogenase (LDH) and aspartate aminotransferase (AST) levels in different myopathy were analyzed. METHODS: The clinical data of 235 cases characterized as myopathic hyper-CK-emia from January 2004 to December 2011 were collected and analyzed. A retrospective analysis of LDH and AST levels according to CK in part of the patients were reviewed. RESULTS: Of the 235 cases, 180 were male and 55 female. According to the age at which hyper-CK-emia was diagnosed, 64 cases were under 6 months, 90 between 6 months and 3 years, 50 between 3 and 6 years and 31 between 6 and 14 years. Their CK levels significantly increased in 162 cases, moderately increased in 31 cases, and slightly increased in 42 cases. The age at which hyper-CK-emia was diagnosed and the CK level had no correlation with muscle weakness and the severity. As to CK levels: Duchenne muscular dystrophy (DMD) > inflammatory myopathies > congenital muscular dystrophy (CMD) > metabolic myopathies. LDH and AST levels: DMD > inflammatory myopathies > metabolic myopathies > CMD. CONCLUSION: Unlike adults, the etiology of myopathic hyper-CK-emia in children is complicated and diverse. The onset type, the degree and duration of hyper-CK-emia are helpful to make the diagnosis. CK increases most significantly in DMD, then in inflammatory myopathies, CMD, and metabolic myopathies. Diagnostic flowchart of myogenic hyper-CK-emia should follow a certain process, and the indications of biochemical tests, metabolic screening, electrophysiological examination, muscle biopsy and genetic testing should be made. Finally, different treatments should be designed according to the etiology.


Assuntos
Creatina Quinase/análise , Diagnóstico Diferencial , Doenças Musculares/enzimologia , Adolescente , Aspartato Aminotransferases/análise , Biópsia , Criança , Pré-Escolar , Feminino , Testes Genéticos , Humanos , L-Lactato Desidrogenase/análise , Masculino , Distrofia Muscular de Duchenne , Estudos Retrospectivos
7.
Zhonghua Er Ke Za Zhi ; 51(1): 47-51, 2013 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-23527931

RESUMO

OBJECTIVE: Periodic paralysis (PP) is one type of skeletal muscle channelopathies characterized by episodic attacks of weakness. It is usually classified into hyperkalemic periodic paralysis (HyperPP), hypokalemic periodic paralysis (HypoPP) and normokalemic periodic paralysis (NormoPP) based on the blood potassium levels. HypoPP is the most common type of these three and NormoPP is the rarest one. The aim of this study was to explore the clinical and genetic features of a Chinese family with normokalemic periodic paralysis (NormoKPP). METHOD: Clinical features of all patients in the family with NormoKPP were analyzed. Genomic DNA was extracted from peripheral blood leukocytes and amplified with PCR. We screened all 24 exons of SCN4A gene and then sequence analysis was performed in those who showed heteroduplex as compared with unaffected controls. RESULT: (1) Fifteen members of the family were clinically diagnosed NormoKPP, and their common features are: onset within infacy, episodic attacks of weakness, the blood potassium levels were within normal ranges, high sodium diet or large dosage of normal saline could attenuate the symptom. One muscle biopsy was performed and examination of light and electronic microscopy showed occasionally degenerating myofibers. (2) Gene of 12 patients were screened and confirmed mutations of SCN4A genes--c. 2111 T > C/p. Thr704Met. CONCLUSION: The study further defined the clinical features of patients with NormoKPP, and molecular genetic analysis found SCN4A gene c. 2111 T > C/p. Thr704Met point mutation contributed to the disease. In line with the autosomal dominant inheritance laws, this family can be diagnosed with periodic paralysis, and be provided with genetic counseling. And the study may also help the clinical diagnosis, guide treatment and genetic counseling of this rare disease in China.


Assuntos
Canalopatias/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Paralisias Periódicas Familiares/genética , Sequência de Aminoácidos , Canalopatias/diagnóstico , Canalopatias/patologia , Criança , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Paralisias Periódicas Familiares/diagnóstico , Paralisias Periódicas Familiares/patologia , Linhagem , Reação em Cadeia da Polimerase , Potássio/sangue
8.
Gene ; 498(2): 332-5, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22326530

RESUMO

UNLABELLED: Niemann-Pick disease type C (NP-C), caused by mutations of either NPC1 or NPC2 gene, is an inherited lysosomal lipid storage disorder that is difficult to be diagnosed and treated. NP-C is rarely reported in China and so far very few literatures are available for Chinese clinical workers. To better characterize this disease in China and improve genetic counseling, mutational analyses of NPC1 gene were carried out in 6 unrelated Chinese patients. METHODS: Clinical data of the probands from 2007 to 2010 were collected and analyzed. All exons of NPC1 were analyzed by direct sequencing. RESULTS: The six cases, four males and two females, included three cases of late infantile subtype and three cases of juvenile subtype. Case one and case six had siblings who suffered from the same disease. The onset of clinical symptoms varied from three to ten years old, and they included progressive cognitive and language impairment, and motion retrogradation. All were caught by focal or generalized seizures from one to four years after the onset. Vertical supranuclear gaze palsy, dysarthria, dysphagia, internal rotation and adduction of bilateral hands and splenomegaly occurred gradually during the disease progression. Five patients had laughter-cataplexy. MRI indicated mild brain atrophy. Sea blue cells and Niemann-Pick cells were presented in bone marrow smears. Activity of acid sphingomyelinase was normal or only slightly lower than controls. Supporting and symptomatic treatments could improve some of the clinical signs. We identified 10 different NPC1 mutations were identified in 12/12 alleles, 3 of which are described for the first time. All mutations were missense mutations, which located throughout the gene with five clustering in the cysteine-rich luminal domain. Homozygous mutation of S865L correlated with a relatively severe juvenile neurological form. CONCLUSIONS: NP-C is a rare autosomal recessive lysosomal storage disease that affects intellectual development of children, causing dementia, vegetative state and eventual death. The awareness of NP-C should be raised in the Chinese population. The typical clinical features of this disease include vertical supranuclear gaze palsy, seizures and cataplexy. Laboratory features include the presence of sea blue cells and Niemann-Pick cells in bone marrow smears. NPC1 mutation can be identified in most of these patients and most of them are missense mutations.


Assuntos
Proteínas de Transporte/genética , Glicoproteínas de Membrana/genética , Mutação de Sentido Incorreto , Doença de Niemann-Pick Tipo C/genética , Grupo com Ancestrais do Continente Asiático/genética , Células da Medula Óssea/patologia , Encéfalo/patologia , Cataplexia/genética , Criança , Pré-Escolar , Éxons , Feminino , Genótipo , Humanos , Masculino , Doença de Niemann-Pick Tipo C/etiologia , Fenótipo
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