Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.152
Filtrar
1.
PLoS Genet ; 16(9): e1009017, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925911

RESUMO

Interpreting rare variants remains a challenge in personal genomics, especially for disorders with several causal genes and for genes that cause multiple disorders. ZNF423 encodes a transcriptional regulatory protein that intersects several developmental pathways. ZNF423 has been implicated in rare neurodevelopmental disorders, consistent with midline brain defects in Zfp423-mutant mice, but pathogenic potential of most patient variants remains uncertain. We engineered ~50 patient-derived and small deletion variants into the highly-conserved mouse ortholog and examined neuroanatomical measures for 791 littermate pairs. Three substitutions previously asserted pathogenic appeared benign, while a fourth was effectively null. Heterozygous premature termination codon (PTC) variants showed mild haploabnormality, consistent with loss-of-function intolerance inferred from human population data. In-frame deletions of specific zinc fingers showed mild to moderate abnormalities, as did low-expression variants. These results affirm the need for functional validation of rare variants in biological context and demonstrate cost-effective modeling of neuroanatomical abnormalities in mice.


Assuntos
Defeitos do Tubo Neural/genética , Proteínas/genética , Alelos , Animais , Encéfalo/patologia , Encefalopatias/genética , Modelos Animais de Doenças , Feminino , Frequência do Gene/genética , Genômica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Malformações do Sistema Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas/metabolismo , Fatores de Transcrição/genética , Dedos de Zinco
2.
Adv Exp Med Biol ; 1255: 231-247, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949404

RESUMO

The single-cell RNA sequencing (scRNA-seq) is a powerful tool for exploring the complexity, clusters, and specific functions of the brain cells. Using scRNA-seq, the heterogeneity and changes in transcriptomic profiles of a single neuron were defined during dynamic development and differentiation of cells in cerebral cortex regions, and in the pathogenesis of neurological diseases. One of the great challenges is that the brain sample is susceptible to interference and confounding. More advanced methodologies of computational systems biology need to be developed to overcome the inherent interference and technical differences in the detection of single-cell signals. It is expected that scRNA-seq will be extended to metabolic profiles of the single neuron cell on basis of transcriptional profiles and regulatory networks. It is also expected if the transcriptional profiles can be integrated with molecular and functional phenomes in a single neuron and with disease-specific phenomes to understand molecular mechanisms of brain development and disease occurrence. scRNA-seq will provide the new emerging neurological disciple of the artificial intelligent single neuron for deep understanding of brain diseases.


Assuntos
Córtex Cerebral/embriologia , Córtex Cerebral/metabolismo , RNA-Seq , Análise de Célula Única , Encefalopatias/genética , Encefalopatias/metabolismo , Encefalopatias/patologia , Córtex Cerebral/citologia , Humanos , Transcriptoma
4.
Nat Commun ; 11(1): 4016, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782260

RESUMO

Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.


Assuntos
Encefalopatias/genética , Encefalopatias/patologia , Tronco Encefálico/anatomia & histologia , Encefalopatias/diagnóstico por imagem , Encefalopatias/metabolismo , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Homologia de Genes , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Imagem por Ressonância Magnética , Herança Multifatorial , Tamanho do Órgão/genética
5.
Artigo em Chinês | MEDLINE | ID: mdl-32746566

RESUMO

Objective: To investigate the association of WWP2 single nucleotide polymorphism (rs3790088, rs4247109) with delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) , and explore the influences of DEACMP genetic predisposition. Methods: From November 2006 to December 2017, 235 DEACMP cases and 429 acute carbon monoxide poisoning (ACMP) cases were selected. All ACMP patients were followed up for more than 90 days without DEACMP. The DNA in all blood samples were extracted with the blood Genome DNA Extraction Kit. The method of Sequenom Mass Array SNP technique was used to detect the genotype and allele of WWP2. All DEACMP patients were assessed every 3 days after hospitalization by the Hasegawa Dementia Scale (HDS) and Activity of Daily Living Scale (ADL) . The distribution of genotypes in conformty with Hardy-Weinderg law was analyzed by goodness-of-fit χ(2) test, and χ(2) test was used for association analysis. Results: For rs3790088, there were 226 DEACMP cases and 414 ACMP cases. For rs4247109, there were 234 DEACMP cases and 428 ACMP cases. For rs3790088 and rs4247109 in WWP2 gene: there were not significant differences in the gene genotype distribution and allele frequency of both DEACMP group and ACMP group (P>0.05) . According to gender, there were not significant differences in WWP2 gene genotype distribution and allele frequency between two female groups and two male groups (P>0.05) . After analysis by genetic model, the genotype distributions in both DEACMP group and ACMP group were not significantly differences in three genetic models (codominant genetic model, recessive genetic model and dominant genetic model, P>0.05) . Conclusion: It has not confirmed the genetic correlation between the two gene single nucleotide polymorphisms (rs3790088, rs4247109) of WWP2 gene and the incidence of DEACMP.


Assuntos
Encefalopatias/genética , Intoxicação por Monóxido de Carbono , Ubiquitina-Proteína Ligases/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
6.
Epilepsia ; 61(7): e71-e78, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32645220

RESUMO

Fibroblast growth-factor homologous factor (FHF1) gene variants have recently been associated with developmental and epileptic encephalopathy (DEE). FHF1 encodes a cytosolic protein that modulates neuronal sodium channel gating. We aim to refine the electroclinical phenotypic spectrum of patients with pathogenic FHF1 variants. We retrospectively collected clinical, genetic, neurophysiologic, and neuroimaging data of 17 patients with FHF1-DEE. Sixteen patients had recurrent heterozygous FHF1 missense variants: 14 had the recurrent p.Arg114His variant and two had a novel likely pathogenic variant p.Gly112Ser. The p.Arg114His variant is associated with an earlier onset and more severe phenotype. One patient carried a chromosomal microduplication involving FHF1. Twelve patients carried a de novo variant, five (29.5%) inherited from parents with gonadic or somatic mosaicism. Seizure onset was between 1 day and 41 months; in 76.5% it was within 30 days. Tonic seizures were the most frequent seizure type. Twelve patients (70.6%) had drug-resistant epilepsy, 14 (82.3%) intellectual disability, and 11 (64.7%) behavioral disturbances. Brain magnetic resonance imaging (MRI) showed mild cerebral and/or cerebellar atrophy in nine patients (52.9%). Overall, our findings expand and refine the clinical, EEG, and imaging phenotype of patients with FHF1-DEE, which is characterized by early onset epilepsy with tonic seizures, associated with moderate to severe ID and psychiatric features.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Fatores de Crescimento de Fibroblastos/genética , Deficiência Intelectual/genética , Fenótipo , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Encefalopatias/diagnóstico por imagem , Encefalopatias/fisiopatologia , Criança , Pré-Escolar , Eletroencefalografia/métodos , Epilepsia/diagnóstico por imagem , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Estudos Retrospectivos , Adulto Jovem
7.
Am J Hum Genet ; 107(2): 364-373, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32707086

RESUMO

We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.


Assuntos
Encefalopatias/genética , Proteínas Mitocondriais/genética , Doenças Neurodegenerativas/genética , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Alelos , Sequência de Aminoácidos , Criança , Feminino , Humanos , Masculino , Mitocôndrias/genética , Linhagem , Fenótipo , Adulto Jovem
8.
J Pharmacol Sci ; 144(2): 83-88, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32709559

RESUMO

Astrocytes generate robust intracellular Ca2+ signals that are assumed to be key regulators of astrocytic function. Among various Ca2+ mobilization mechanisms, Ca2+ release from the endoplasmic reticulum (ER) via the inositol 1,4,5-trisphosphate receptor (IP3R) has attracted attention as a major component of astrocytic Ca2+ signaling. Manipulation of astrocytic IP3-Ca2+ signaling, such as genetic deletion of the type 2 IP3R, has revealed multifaceted roles of astrocytic ER Ca2+ release in health and disease. Recent developments in Ca2+ imaging techniques including ER intraluminal Ca2+ imaging have been indispensable in determining the physiological and pathophysiological significance of astrocytic ER Ca2+ release via IP3Rs. Beneficial and detrimental roles of IP3R-dependent Ca2+ release in astrocytes have been revealed in wide variety of disorders in the brain, strongly suggesting astrocytic IP3-Ca2+ signaling as a novel and promising therapeutic target.


Assuntos
Astrócitos/metabolismo , Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/fisiologia , Animais , Encefalopatias/etiologia , Encefalopatias/genética , Encefalopatias/terapia , Deleção de Genes , Humanos , Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Imagem Molecular , Terapia de Alvo Molecular
10.
Zhonghua Er Ke Za Zhi ; 58(6): 493-498, 2020 Jun 02.
Artigo em Chinês | MEDLINE | ID: mdl-32521962

RESUMO

Objective: To investigate the clinical and genetic characteristics of developmental and epileptic encephalopathy (DEE) caused by syntaxin-binding protein 1 (STXBP1) gene mutation. Methods: The clinical data, gene variation and treatment outcome of 15 children with STXBP1 encephalopathy admitted to Children's Hospital Affiliated to Capital Institute of Pediatrics from January 2014 to June 2019 were analyzed retrospectively. Results: Among 15 patients, 11 were male and 4 were female, age ranged from 2 months to 69 months. The clinical manifestations of 14 children were epilepsy and developmental delay (DD) and the remaining one showed developmental delay without seizure. The onset age of epilepsy ranged from two days to 19 months and 11 of them experienced the first attack before 1 year of age. The common seizure types were epileptic spasms and tonic seizures. Seven patients were diagnosed with Ohtahara syndrome or West syndrome. Epileptic form discharges were observed in the interictal electroencephalograms (EEG) of 11 patients, including multifocal discharges, suppression-burst and hypsarrhythmia. The brain magnetic resonance imaging of 7 children were abnormal, including myelin dysplasia, less white matter, lack of corpus callosum or hypoplasia. The follow-up time ranged from 2 months to 57 months, after the last follow-up, 3 cases were seizure free, 6 children showed partial response and the other 5 patients had no response on multitherapy. Six of 8 patients showed good responses to levetiracetam (LEV) monotherapy or in combination with other antiepileptic drugs (AEDs). Vigabatrin (VGB) was applied to 5 patients with epileptic spasms and 4 of them showed response. All patients showed different degrees of developmental delay while four of them showed autistic features. STXBP1 gene mutations were identified in all cases and there were 15 types of gene variations, including 8 missense mutations, 1 nonsense mutation, 5 frame shift mutations and 1 complex mutation. Five novel mutations were unreported before, including c.1193A>G, c.172delG, c.1769C>T, c.1038_1039delCC, c.348_351dupTGAA. Conclusions: Development delay and epilepsy are the major and independent clinical phenotypes in children with STXBP1 encephalopathy. The variation of STXBP1 gene is mainly de novo. Levetiracetam and vigabatrin may be more effective in epilepsy control than other AEDs.


Assuntos
Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Eletroencefalografia , Epilepsia/genética , Proteínas Munc18/genética , Espasmos Infantis/genética , Encefalopatias/diagnóstico , Pré-Escolar , Deficiências do Desenvolvimento/etiologia , Epilepsia/etiologia , Feminino , Humanos , Lactente , Masculino , Mutação , Mutação Puntual , Estudos Retrospectivos , Espasmos Infantis/etiologia
11.
Muscle Nerve ; 62(2): 266-271, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32363625

RESUMO

BACKGROUND: Biallelic mutations in TBC1-domain containing kinase (TBCK) lead to hypotonia, global developmental delay with severe cognitive and motor deficits, and variable presentation of dysmorphic facial features and brain malformations. It remains unclear whether hypotonia in these individuals is purely neurogenic, or also caused by progressive muscle disease. METHODS: Whole exome sequencing was performed on a family diagnosed with nonspecific myopathic changes by means of histological analysis and immunohistochemistry of muscle biopsy samples. RESULTS: A novel homozygous truncation in TBCK was found in two sisters diagnosed with muscle disease and severe psychomotor delay. TBCK was completely absent in these patients. CONCLUSIONS: Our findings identify a novel early truncating variant in TBCK associated with a severe presentation and add muscle disease to the variability of phenotypes associated with TBCK mutations. Inconsistent genotype/phenotype correlation could be ascribed to the multiple roles of TBCK in intracellular signaling and endolysosomal function in different tissues.


Assuntos
Encefalopatias/genética , Mutação com Perda de Função , Hipotonia Muscular/genética , Músculo Esquelético/patologia , Doenças Musculares/genética , Proteínas Serina-Treonina Quinases/genética , Transtornos Psicomotores/genética , Convulsões/genética , Adolescente , Encéfalo/diagnóstico por imagem , Encefalopatias/diagnóstico por imagem , Criança , Deficiências do Desenvolvimento/genética , Feminino , Homozigoto , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Debilidade Muscular/genética , Debilidade Muscular/patologia , Doenças Musculares/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Reflexo Anormal/genética , Índice de Gravidade de Doença , Irmãos , Síndrome , Sequenciamento Completo do Exoma
12.
Am J Hum Genet ; 106(5): 717-725, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32330417

RESUMO

We identified three unrelated individuals with de novo missense variants in CDK19, encoding a cyclin-dependent kinase protein family member that predominantly regulates gene transcription. These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features. CDK19 is conserved between vertebrate and invertebrate model organisms, but currently abnormalities in CDK19 are not known to be associated with a human disorder. Loss of Cdk8, the fly homolog of CDK19, causes larval lethality, which is suppressed by expression of human CDK19 reference cDNA. In contrast, the CDK19 p.Tyr32His and p.Thr196Ala variants identified in the affected individuals fail to rescue the loss of Cdk8 and behave as null alleles. Additionally, neuronal RNAi-mediated knockdown of Cdk8 in flies results in semi-lethality. The few eclosing flies exhibit severe seizures and a reduced lifespan. Both phenotypes are fully suppressed by moderate expression of the CDK19 reference cDNA but not by expression of the two variants. Finally, loss of Cdk8 causes an obvious loss of boutons and synapses at larval neuromuscular junctions (NMJs). Together, our findings demonstrate that human CDK19 fully replaces the function of Cdk8 in the fly, the human disease-associated CDK19 variants behave as strong loss-of-function variants, and deleterious CDK19 variants underlie a syndromic neurodevelopmental disorder.


Assuntos
Encefalopatias/genética , Quinases Ciclina-Dependentes/genética , Epilepsia Generalizada/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Adulto , Sequência de Aminoácidos , Animais , Pré-Escolar , Quinase 8 Dependente de Ciclina/deficiência , Quinase 8 Dependente de Ciclina/genética , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Junção Neuromuscular , Doenças Raras/genética , Convulsões/genética , Síndrome , Adulto Jovem
15.
Lancet Child Adolesc Health ; 4(7): 536-547, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32142633

RESUMO

Voltage-gated sodium channels are essential for excitability of skeletal muscle fibres and neurons. An increasing number of disabling or fatal paediatric neurological disorders linked to mutations of voltage-gated sodium channel genes are recognised. Muscle phenotypes include episodic paralysis, myotonia, neonatal hypotonia, respiratory compromise, laryngospasm or stridor, congenital myasthenia, and myopathy. Evidence suggests a possible link between sodium channel dysfunction and sudden infant death. Increasingly recognised phenotypes of brain sodium channelopathies include several epilepsy disorders and complex encephalopathies. Together, these early-onset muscle and brain phenotypes have a substantial morbidity and a considerable mortality. Important advances in understanding the pathophysiological mechanisms underlying these channelopathies have helped to identify effective targeted therapies. The availability of effective treatments underlines the importance of increasing clinical awareness and the need to achieve a precise genetic diagnosis. In this Review, we describe the expanded range of phenotypes of muscle and brain sodium channelopathies and the underlying knowledge regarding mechanisms of sodium channel dysfunction. We also outline a diagnostic approach and review the available treatment options.


Assuntos
Encefalopatias/diagnóstico , Encefalopatias/genética , Canalopatias/diagnóstico , Canalopatias/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Canais de Sódio Disparados por Voltagem/genética , Transtorno do Espectro Autista/genética , Encefalopatias/terapia , Canalopatias/terapia , Morte Súbita/etiologia , Testes Genéticos , Humanos , Deficiência Intelectual/genética , Doenças Musculares/terapia , Prognóstico
16.
Am J Hum Genet ; 106(3): 412-421, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142645

RESUMO

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification.


Assuntos
Idade de Início , Alelos , Encefalopatias/genética , Calcinose/genética , Moléculas de Adesão Celular/genética , Genes Recessivos , Adolescente , Adulto , Animais , Encefalopatias/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Criança , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Linhagem
17.
Am J Hum Genet ; 106(4): 559-569, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32197075

RESUMO

Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat-containing protein that uniquely associates with latent transforming growth factor beta-1 (TGF- ß1) and anchors it on the cell surface; this anchoring is required for activation of TGF-ß1 in macrophages and microglia. We report six individuals from four families with bi-allelic variants in NRROS. All affected individuals had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination. The clinical course in affected individuals began with normal development or mild developmental delay, and the onset of seizures occurred within the first year of life, followed by developmental regression. Intracranial calcification was detected in three individuals. The phenotypic features in affected individuals are consistent with those observed in the Nrros knockout mouse, and they overlap with those seen in the human condition associated with TGF-ß1 deficiency. The disease-causing NRROS variants involve two significant functional NRROS domains. These variants result in aberrant NRROS proteins with impaired ability to anchor latent TGF-ß1 on the cell surface. Using confocal microscopy in HEK293T cells, we demonstrate that wild-type and mutant NRROS proteins co-localize with latent TGF-ß1 intracellularly. However, using flow cytometry, we show that our mutant NRROS proteins fail to anchor latent TGF-ß1 at the cell surface in comparison to wild-type NRROS. Moreover, wild-type NRROS rescues the defect of our disease-associated mutants in presenting latent TGF-ß1 to the cell surface. Taken together, our findings suggest that loss of NRROS function causes a severe childhood-onset neurodegenerative condition with features suggestive of a disordered response to inflammation.


Assuntos
Encefalopatias/genética , Calcinose/genética , Variação Genética/genética , Proteínas de Ligação a TGF-beta Latente/genética , Doenças Neurodegenerativas/genética , Fator de Crescimento Transformador beta1/genética , Alelos , Feminino , Células HEK293 , Humanos , Lactente , Macrófagos/patologia , Masculino , Microglia/patologia
18.
Nat Genet ; 52(4): 363-369, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203467

RESUMO

The genetic architecture of each individual comprises common and rare variants that, acting alone and in combination, confer risk of disease. The cell-type-specific and/or context-dependent functional consequences of the risk variants linked to brain disease must be resolved. Coupling human induced pluripotent stem cell (hiPSC)-based technology with CRISPR-based genome engineering facilitates precise isogenic comparisons of variants across genetic backgrounds. Although functional-validation studies are typically performed on one variant in isolation and in one cell type at a time, complex genetic diseases require multiplexed gene perturbations to interrogate combinations of genes and resolve physiologically relevant disease biology. Our aim is to discuss advances at the intersection of genomics, hiPSCs and CRISPR. A better understanding of the molecular mechanisms underlying disease risk will improve genetic diagnosis, drive phenotypic drug discovery and pave the way toward precision medicine.


Assuntos
Encefalopatias/genética , Animais , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Genoma/genética , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Medicina de Precisão/métodos
19.
Nat Neurosci ; 23(4): 583-593, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32152537

RESUMO

Most risk variants for brain disorders identified by genome-wide association studies reside in the noncoding genome, which makes deciphering biological mechanisms difficult. A commonly used tool, multimarker analysis of genomic annotation (MAGMA), addresses this issue by aggregating single nucleotide polymorphism associations to nearest genes. Here we developed a platform, Hi-C-coupled MAGMA (H-MAGMA), that advances MAGMA by incorporating chromatin interaction profiles from human brain tissue across two developmental epochs and two brain cell types. By analyzing gene regulatory relationships in the disease-relevant tissue, H-MAGMA identified neurobiologically relevant target genes. We applied H-MAGMA to five psychiatric disorders and four neurodegenerative disorders to interrogate biological pathways, developmental windows and cell types implicated for each disorder. Psychiatric-disorder risk genes tended to be expressed during mid-gestation and in excitatory neurons, whereas neurodegenerative-disorder risk genes showed increasing expression over time and more diverse cell-type specificities. H-MAGMA adds to existing analytic frameworks to help identify the neurobiological principles of brain disorders.


Assuntos
Encefalopatias/genética , Encéfalo/metabolismo , Cromatina/metabolismo , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Encefalopatias/metabolismo , Genômica , Humanos , Fatores de Risco
20.
Epileptic Disord ; 22(1): 103-109, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32043468

RESUMO

Mutations in ATP1A3 have been found to cause rapid-onset dystonia Parkinsonism, alternating hemiplegia of childhood, epileptic encephalopathy and other syndromes. We report a four-year, nine-month-old boy with episodes of frequent and recurrent status epilepticus, who first began having generalized tonic-clonic seizures at four months of age. Development was normal until the age of four months, and markedly slowed down after the onset of seizures. Between the age of seven months and two and a half years, the patient had recurrent attacks of unilateral and bilateral hemiplegia. At the age of 21 months, after a febrile illness with status epilepticus, he regressed and developed continuous severe dystonia and bradykinesia with superimposed intermittent painful dystonic spasms. Extensive neurological and genetic workup revealed a de novo p.V589F ATP1A3 mutation (NM_152296.5:c.1765G>T, NC_000019.9:g.42482344C>A). This is a novel mutation associated with a novel phenotype that shares features with epileptic encephalopathy, alternating hemiplegia of childhood, and rapid-onset dystonia Parkinsonism.


Assuntos
Encefalopatias , Distúrbios Distônicos , Epilepsia , Hemiplegia , ATPase Trocadora de Sódio-Potássio/genética , Encefalopatias/genética , Encefalopatias/fisiopatologia , Pré-Escolar , Distúrbios Distônicos/genética , Distúrbios Distônicos/fisiopatologia , Epilepsia/genética , Epilepsia/fisiopatologia , Hemiplegia/genética , Hemiplegia/fisiopatologia , Humanos , Masculino , Fenótipo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA