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1.
Sci Adv ; 5(9): eaax2166, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31579823

RESUMO

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.

2.
Nat Commun ; 10(1): 4679, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31616000

RESUMO

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.

3.
J Dermatol ; 46(8): 731-733, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31241787

RESUMO

Hypohidrotic ectodermal dysplasia (HED) is a rare hereditary disorder that affects tissues derived from the ectoderm including hair, teeth and sweat glands. EDA is the major causative gene of HED. This study recruited a Chinese family with HED, including a male proband and his mother with a fetus. The proband had typical clinical features of HED and the mother had identical but milder features. Interestingly, some phenotypes of the mother appeared asymmetrically between the right and left side of the body that were not reported in previous studies. Targeted sequencing was performed in the proband and a novel frame-shift mutation (NM_001399.4: c.381_382delinsG, p.Q128Rfs*9) in EDA was found. Sanger sequencing validated the mutation and identified the same mutation in the mother. Our study expands the clinical and genetic spectrum of EDA-related disorders and reports new asymmetrical phenotypes in a female.


Assuntos
Displasia Ectodérmica Anidrótica Tipo 1/genética , Ectodisplasinas/genética , Genes Ligados ao Cromossomo X/genética , Fenótipo , Adulto , Criança , Análise Mutacional de DNA , Displasia Ectodérmica Anidrótica Tipo 1/diagnóstico , Feminino , Mutação da Fase de Leitura , Aconselhamento Genético , Hemizigoto , Heterozigoto , Humanos , Masculino
4.
Biochem Biophys Res Commun ; 514(4): 1122-1127, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31101334

RESUMO

Toxin-antitoxin (TA) systems play critical roles in the environment adaptation of bacteria. Allosteric coupling between the N-terminal DNA-binding domain and the C-terminal toxin-binding domain of antitoxins contributes to conditional cooperativity in the functioning of type II TA. Herein, using circular dichroism (CD), nuclear magnetic resonance (NMR), X-ray crystallography, and size exclusion chromatography (SEC), the structure and DNA binding of CopASO, a newly identified type II antitoxin in Shewanella oneidensis, were investigated. Our data show that CopASO is a typical RHH antitoxin with an ordered N-terminal domain and a disordered C-terminal domain, and furthermore indicate that the C-terminal domain facilitates DNA binding of the N-terminal domain, which in turn induces the C-terminal domain to fold and associate.

5.
Mol Autism ; 9: 64, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30564305

RESUMO

Background: We previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype-phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent. Methods: We sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes. Results: We validated recurrent, LGD, de novo mutations (DNMs) in 13 genes. We identified a potential novel risk gene (ZNF292), one novel gene with recurrent LGD DNMs (RALGAPB), as well as genes associated with macrocephaly (GIGYF2 and WDFY3). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes. Conclusions: We identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk.


Assuntos
Transtorno do Espectro Autista/genética , Modelos Genéticos , Herança Multifatorial , Mutação , Adulto , Criança , Feminino , Humanos , Masculino , Linhagem , Locos de Características Quantitativas
6.
Sci Rep ; 7: 44155, 2017 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-28281572

RESUMO

Autism spectrum disorder (ASD) describes a group of neurodevelopmental disorders with high heritability, although the underlying genetic determinants of ASDs remain largely unknown. Large-scale whole-genome studies of copy number variation in Han Chinese samples are still lacking. We performed a genome-wide copy number variation analysis of 343 ASD trios, 203 patients with sporadic cases and 988 controls in a Chinese population using Illumina genotyping platforms to identify CNVs and related genes that may contribute to ASD risk. We identified 32 rare CNVs larger than 1 Mb in 31 patients. ASD patients were found to carry a higher global burden of rare, large CNVs than controls. Recurrent de novo or case-private CNVs were found at 15q11-13, Xp22.3, 15q13.1-13.2, 3p26.3 and 2p12. The de novo 15q11-13 duplication was more prevalent in this Chinese population than in those with European ancestry. Several genes, including GRAMD2 and STAM, were implicated as novel ASD risk genes when integrating whole-genome CNVs and whole-exome sequencing data. We also identified several CNVs that include known ASD genes (SHANK3, CDH10, CSMD1) or genes involved in nervous system development (NYAP2, ST6GAL2, GRM6). Besides, our study also implicated Contactins-NYAPs-WAVE1 pathway in ASD pathogenesis. Our findings identify ASD-related CNVs in a Chinese population and implicate novel ASD risk genes and related pathway for further study.


Assuntos
Transtorno do Espectro Autista/genética , Cromossomos Humanos/genética , Exoma , Dosagem de Genes , Estudo de Associação Genômica Ampla , Adulto , Grupo com Ancestrais do Continente Asiático , Criança , Pré-Escolar , China , Feminino , Humanos , Masculino
7.
Zhonghua Liu Xing Bing Xue Za Zhi ; 23(5): 356-9, 2002 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-12482366

RESUMO

OBJECTIVE: To study iodine nutrition of pregnant women in different occasions and thyroid function of their neonates. METHODS: Urinary iodine of pregnant women and their serum T(3), T(4), FT(3), FT(4) were determined by chloric acid-digestion thermostatic assay and RIA, TSH determination by IRMA; neonatal umbilical cord blood TSH was determined by ELISA. RESULTS: Median urinary iodine of pregnant women were 206.3 microg/L, 161.4 microg/L, 203.3 microg/L at 10 - 14 (first occasion), 23 - 27 (second occasion) and 39 - 40 (third occasion) week but the percentage that lower than 100 microg/L were 14.6%, 17.1%, 11.1% respectively. Serum T(3), T(4) of pregnant women was significantly higher than those women of premarital health inspection (PHIW, P < 0.001). The difference of serum T(3), T(4) of pregnant women at 10 - 14 and 39 - 40 week was not significant. Serum FT(3), FT(4) of pregnant women at 39 - 40 week were 2.61 +/- 0.47 pmol/L and 5.50 +/- 1.57 pmol/L respectively. The difference of serum TSH concentration at third occasion and first occasion of pre-pregnancy was significant but the difference of TSH frequency distribution in three groups was not significant (chi(2) = 1.138, P > 0.5). Blood TSH median neonatal umbilical cord was 1.99 mU/L but the percentage that higher than 5 mU/L was 9.4%. CONCLUSION: For those areas with high iodized salt coverage, pregnant women had had sufficient iodine supplement and good thyroid function. The percentage of neonates from iodine sufficient pregnant women with TSH > 5 mU/L was lower than 10%. Using the normal range of nonpregnant FT(3) and FT(4) to estimate the thyroid function of pregnant women could cause mis diagnosis.


Assuntos
Iodo/urina , Glândula Tireoide/fisiologia , Feminino , Sangue Fetal/química , Humanos , Recém-Nascido , Gravidez , Hormônios Tireóideos/sangue , Tireotropina/sangue
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