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1.
Nat Commun ; 10(1): 3094, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300657

RESUMO

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.


Assuntos
Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Receptores de AMPA/genética , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Heterozigoto , Humanos , Lactente , Mutação com Perda de Função , Imagem por Ressonância Magnética , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Adulto Jovem
2.
Cell Mol Life Sci ; 76(19): 3827-3841, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302748

RESUMO

The Tousled-like kinases (TLKs) are an evolutionarily conserved family of serine-threonine kinases that have been implicated in DNA replication, DNA repair, transcription, chromatin structure, viral latency, cell cycle checkpoint control and chromosomal stability in various organisms. The functions of the TLKs appear to depend largely on their ability to regulate the H3/H4 histone chaperone ASF1, although numerous TLK substrates have been proposed. Over the last few years, a clearer picture of TLK function has emerged through the identification of new partners, the definition of specific roles in development and the elucidation of their structural and biochemical properties. In addition, the TLKs have been clearly linked to human disease; both TLK1 and TLK2 are frequently amplified in human cancers and TLK2 mutations have been identified in patients with neurodevelopmental disorders characterized by intellectual disability (ID), autism spectrum disorder (ASD) and microcephaly. A better understanding of the substrates, regulation and diverse roles of the TLKs is needed to understand their functions in neurodevelopment and determine if they are viable targets for cancer therapy. In this review, we will summarize current knowledge of TLK biology and its potential implications in development and disease.


Assuntos
Instabilidade Genômica , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Epigênese Genética , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Transtornos do Neurodesenvolvimento/genética , Domínios Proteicos , Proteínas Quinases/química , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia
3.
BMC Med Genet ; 20(1): 95, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151415

RESUMO

BACKGROUND: Tubulinopathies result from mutations in tubulin genes, including TUBG1, responsible for cell microtubules, are characterized by brain development abnormalities, microcephaly, early-onset epilepsy, and motor impairment. Only eleven patients with TUBG1 mutations have been previously described in literature to our knowledge. Here we present two new patients with novel de novo TUBG1 mutations and review other cases in the literature. CASE PRESENTATIONS: Both patients have microcephaly and intellectual disability. Patient B further fits a more typical presentation, with well-controlled epilepsy and mild hypertonia, whereas Patient A's presentation is much milder without these other features. CONCLUSION: This report expands the spectrum of TUBG1 mutation manifestations, suggesting the possibility of less severe phenotypes for patients and families, and influencing genetic counselling strategies.


Assuntos
Predisposição Genética para Doença/genética , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Tubulina (Proteína)/genética , Criança , Feminino , Humanos , Lactente , Masculino , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Índice de Gravidade de Doença
4.
Nat Commun ; 10(1): 2396, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160561

RESUMO

Modern genetic studies indicate that human brain evolution is driven primarily by changes in gene regulation, which requires understanding the biological function of largely non-coding gene regulatory elements, many of which act in tissue specific manner. We leverage chromatin interaction profiles in human fetal and adult cortex to assign three classes of human-evolved elements to putative target genes. We find that human-evolved elements involving DNA sequence changes and those involving epigenetic changes are associated with human-specific gene regulation via effects on different classes of genes representing distinct biological pathways. However, both types of human-evolved elements converge on specific cell types and laminae involved in cerebral cortical expansion. Moreover, human evolved elements interact with neurodevelopmental disease risk genes, and genes with a high level of evolutionary constraint, highlighting a relationship between brain evolution and vulnerability to disorders affecting cognition and behavior. These results provide novel insights into gene regulatory mechanisms driving the evolution of human cognition and mechanisms of vulnerability to neuropsychiatric conditions.


Assuntos
Córtex Cerebral/embriologia , Epigênese Genética/genética , Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento/genética , Células-Tronco Neurais/metabolismo , Transtornos do Neurodesenvolvimento/genética , Encéfalo/embriologia , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Predisposição Genética para Doença , Humanos , Elementos Reguladores de Transcrição/genética
5.
Gene ; 706: 162-171, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31085274

RESUMO

In clinical genetics, the need to discriminate between benign and pathogenic variants identified in patients with neurodevelopmental disorders is an absolute necessity. Copy number variants (CNVs) of small size can enable the identification of genes that are critical for neurologic development. However, assigning a definite association with a specific disorder is a difficult task. Among 328 trios analyzed over seven years of activity in a single laboratory, we identified 19 unrelated patients (5.8%) who carried a small (<500 kb) de novo CNV. Four patients had an additional independent de novo CNV. Nine had a variant that could be assigned as definitely pathogenic, whereas the remaining CNVs were considered as variants of unknown significance (VUS). We report clinical and molecular findings of patients harboring VUS. We reviewed the medical literature available for genes impacted by CNVs, obtained the probability of truncating loss-of-function intolerance, and compared overlapping CNVs reported in databases. The classification of small non-recurrent CNVs remains difficult but, among our findings, we provide support for a role of SND1 in the susceptibility of autism, describe a new case of the rare 17p13.1 microduplication syndrome, and report an X-linked duplication involving KIF4A and DLG3 as a likely cause of epilepsy.


Assuntos
Variações do Número de Cópias de DNA/genética , Transtornos do Neurodesenvolvimento/genética , Adulto , Transtorno Autístico/genética , Criança , Pré-Escolar , Epilepsia/genética , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Cinesina/genética , Masculino , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Fatores de Transcrição/genética
6.
Proc Natl Acad Sci U S A ; 116(14): 7083-7088, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30890645

RESUMO

Maternal infection during pregnancy increases risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, expression of sEH (or EPHX2) mRNA in induced pluripotent stem cell-derived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression of EPHX2 mRNA in postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor, in juvenile offspring from prenatal day (P) 28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV immunoreactivity in the medial prefrontal cortex of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH represents a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.


Assuntos
Epóxido Hidrolases/biossíntese , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Exposição Materna/efeitos adversos , Transtornos do Neurodesenvolvimento , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal , Efeitos Tardios da Exposição Pré-Natal , Esquizofrenia , Animais , Epóxido Hidrolases/genética , Feminino , Camundongos , Transtornos do Neurodesenvolvimento/induzido quimicamente , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/prevenção & controle , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Esquizofrenia/induzido quimicamente , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/prevenção & controle
7.
Early Hum Dev ; 131: 63-74, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30870624

RESUMO

BACKGROUND: Every year, an estimated 15 million babies are born preterm (<37 weeks' gestational age [GA]) globally. These preterm infants are exposed to repeated stressful and often painful procedures as part of routine life-saving care within the neonatal intensive care unit (NICU). Preterm birth continues to be a major health issue associated with increased risk of neurodevelopmental and behavioral disorders such as cerebral palsy, cognitive impairment, autism spectrum disorders and psychiatric disease. OBJECTIVE: This paper identifies epigenetic alterations and incidence of telomere erosion that have been studied in preterm infants while in the NICU and as a long-term outcome measure. Better understanding of epigenetic alterations and telomere erosion might aid in early detection and prevention/alleviation of the negative effects of cumulative painful/stressful experiences in this population. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards were used to guide this review. Systematic searches of databases included PubMed, CINAHL, SCOPUS and PsychInfo. RESULTS: Twenty-one studies were included, appraised and then synthesized into a narrative summary. DISCUSSION: Several putative epigenetic markers were identified although there was a paucity of studies related to telomere length. The interaction of disease entity combined with therapeutic interventions intended to treat may inadvertently increase infant allostatic load or ability to adapt to stress. Future research should include not only human studies but leverage newly available large data sets to conduct additional analysis.


Assuntos
Epigênese Genética , Recém-Nascido Prematuro/fisiologia , Telômero/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Humanos , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Fator de Crescimento Insulin-Like II/genética , Unidades de Terapia Intensiva Neonatal , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Inibidor de NF-kappaB alfa/genética , Transtornos do Neurodesenvolvimento/genética , Receptores de Glucocorticoides/genética , Estresse Fisiológico/genética , Proteínas de Ligação a Tacrolimo/genética
8.
Methods Mol Biol ; 1942: 101-121, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30900179

RESUMO

Patient-derived or genomically modified human induced pluripotent stem cells (iPSCs) offer the opportunity to study neurodevelopmental and neurodegenerative disorders. Overexpression of certain neurogenic transcription factors (TFs) in iPSCs can induce efficient differentiation into homogeneous populations of the disease-relevant neuronal cell types. Here we provide protocols for genomic manipulations of iPSCs by CRISPR/Cas9. We also introduce two methods, based on lentiviral delivery and the piggyBac transposon system, to stably integrate neurogenic TFs into human iPSCs. Furthermore, we describe the TF-mediated neuronal differentiation and maturation in combination with astrocyte cocultures.


Assuntos
Astrócitos/citologia , Sistemas CRISPR-Cas , Células-Tronco Pluripotentes Induzidas/citologia , Doenças Neurodegenerativas/terapia , Transtornos do Neurodesenvolvimento/terapia , Neurônios/citologia , Fatores de Transcrição/genética , Diferenciação Celular , Técnicas de Cocultura , Humanos , Células-Tronco Pluripotentes Induzidas/transplante , Doenças Neurodegenerativas/genética , Transtornos do Neurodesenvolvimento/genética , Neurônios/transplante , Fatores de Transcrição/antagonistas & inibidores
9.
Epigenetics Chromatin ; 12(1): 19, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30898143

RESUMO

The ATP-dependent chromatin remodelling complex BAF (= mammalian SWI/SNF complex) is crucial for the regulation of gene expression and differentiation. In the course of evolution from yeast to mammals, the BAF complex evolved an immense complexity with a high number of subunits encoded by gene families. In this way, tissue-specific BAF function and regulation of development begin with the combinatorial assembly of distinct BAF complexes such as esBAF, npBAF and nBAF. Furthermore, whole-genome sequencing reveals the tremendous role BAF complex mutations have in both neurodevelopmental disorders and human malignancies. Therefore, gaining a more elaborate insight into how BAF complex assembly influences its function and which role distinct subunits play, will hopefully give rise to a better understanding of disease pathogenesis and ultimately to new treatments for many human diseases.


Assuntos
Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/metabolismo , Epigênese Genética , Animais , Eucariotos/genética , Eucariotos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo
10.
Int J Mol Sci ; 20(6)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875831

RESUMO

For the past few years there has been an exponential increase in the use of animal models to confirm the pathogenicity of candidate disease-causing genetic variants found in patients. One such animal model is the zebrafish. Despite being a non-mammalian animal, the zebrafish model has proven its potential in recapitulating the phenotypes of many different human genetic disorders. This review will focus on recent advances in the modeling of neurodevelopmental disorders in zebrafish, covering aspects from early brain development to techniques used for modulating gene expression, as well as how to best characterize the resulting phenotypes. We also review other existing models of neurodevelopmental disorders, and the current efforts in developing and testing compounds with potential therapeutic value.


Assuntos
Transtornos do Neurodesenvolvimento/patologia , Peixe-Zebra , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Transtornos do Neurodesenvolvimento/genética , Fenótipo
11.
Nat Commun ; 10(1): 707, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755602

RESUMO

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.


Assuntos
Epilepsia/genética , Mutação , Valina-tRNA Ligase/genética , Alelos , Anticódon , Criança , Pré-Escolar , Progressão da Doença , Epilepsia/enzimologia , Epilepsia/patologia , Feminino , Predisposição Genética para Doença , Humanos , Estudos Longitudinais , Mutação com Perda de Função , Masculino , Microcefalia/enzimologia , Microcefalia/genética , Modelos Moleculares , Transtornos do Neurodesenvolvimento/enzimologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Linhagem , Biossíntese de Proteínas , Domínios e Motivos de Interação entre Proteínas , RNA de Transferência/genética , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma
12.
Trials ; 20(1): 112, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736834

RESUMO

BACKGROUND: Children born to parents with a severe mental illness, like schizophrenia, bipolar disorder, or major recurrent depression, have an increased risk of developing a mental illness themselves during life. These children are also more likely to have developmental delays, cognitive disabilities, or social problems, and they may have a higher risk than the background population of experiencing adverse life events. This is due to both genetic and environmental factors, but despite the well-documented increased risk for children with a familial high risk, no family-based early intervention has been developed for them. This study aims to investigate the effect of an early intervention that focuses on reducing risk and increasing resilience for children in families where at least one parent has a severe mental illness. METHODS/DESIGN: The study is a randomized clinical trial with 100 children aged 6-12 with familial high risk. It is performed in the context of the Danish health-care system. Families will be recruited from registers or be referred from the primary sector or hospitals. The children and their parents will be assessed at baseline and thereafter randomized and allocated to either treatment as usual or VIA Family. The intervention group will be assigned to a multidisciplinary team of specialists from adult mental health services, child and adolescent mental health services, and social services. This team will provide the basic treatment elements: case management, psychoeducation for the whole family, parental training, a safety plan, and potentially an early intervention if the child has mental problems. The study period is 18 months for both groups, and all participants will be assessed at baseline and after 18 months. The primary outcome measure will be daily functioning of the child, and the secondary measures are the psychopathology of the child, days of absence from school, family functioning, child's home environment, and parental stress. DISCUSSION: This study is to our knowledge the first to explore the effects of a multidisciplinary team intervention that provides an intensive and flexible support to match the families' needs for children with a familial high risk for severe mental illness. The study will provide important knowledge about the potential for increasing resilience and reducing risk for children by supporting the whole family. However, a longer follow-up period may be needed. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03497663 . Registered on 13 April 2018.


Assuntos
Comportamento Infantil , Intervenção Médica Precoce/métodos , Terapia Familiar , Transtornos do Neurodesenvolvimento/prevenção & controle , Resiliência Psicológica , Fatores Etários , Criança , Dinamarca , Estudos de Equivalência como Asunto , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/psicologia , Poder Familiar , Pais/educação , Pais/psicologia , Linhagem , Fenótipo , Medição de Risco , Fatores de Risco , Apoio Social , Fatores de Tempo , Resultado do Tratamento
13.
Nat Commun ; 10(1): 708, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755616

RESUMO

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.


Assuntos
Encefalopatias/genética , Microcefalia/genética , Valina-tRNA Ligase/genética , Alelos , Animais , Encefalopatias/enzimologia , Encefalopatias/patologia , Linhagem Celular , Modelos Animais de Doenças , Epilepsia/enzimologia , Epilepsia/genética , Epilepsia/patologia , Feminino , Fibroblastos , Técnicas de Inativação de Genes , Predisposição Genética para Doença , Humanos , Mutação com Perda de Função , Masculino , Microcefalia/enzimologia , Microcefalia/patologia , Modelos Moleculares , Transtornos do Neurodesenvolvimento/enzimologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Linhagem , Prosencéfalo/patologia , Peixe-Zebra
14.
Psychiatr Genet ; 29(3): 91-94, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30741786

RESUMO

The sodium voltage-gated channel α subunit 2 (SCN2A) gene encodes a subunit of sodium voltage-gated channels expressed primarily in the central nervous system that are responsible for action potential initiation and propagation in excitable cells. SCN2A mutations underlie a spectrum of distinct phenotypes, including seizure disorders, neurodevelopmental disorders, and rarer instances of episodic ataxia and schizophrenia. We report on a 38-year-old patient with adult-onset psychotic symptoms on a background of infantile-onset seizures, autistic features and episodic ataxia. Whole-exome sequencing revealed a de-novo novel SCN2A mutation (c.4966T > C, p.Ser1656Pro). This and other SCN2A mutations associated with the schizophrenia phenotype overlap those seen in neurodevelopmental disorders, suggesting a common underlying mechanism. This is the first report of a patient with the entire known SCN2A phenotypic spectrum. We highlight the importance of recognizing the psychiatric phenotypes associated with SCN2A mutations and that the phenotypic spectrum is more fluid, and less categorical, than previously thought.


Assuntos
Canal de Sódio Disparado por Voltagem NAV1.2/genética , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Adulto , Ataxia/genética , Epilepsia/genética , Humanos , Masculino , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.2/fisiologia , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Psicologia do Esquizofrênico , Sequenciamento Completo do Exoma
15.
Nat Commun ; 10(1): 928, 2019 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-30804331

RESUMO

Dosage of key regulators impinge on developmental disorders such as FOXG1 syndrome. Since neither knock-out nor knock-down strategy assures flexible and precise protein abundance control, to study hypomorphic or haploinsufficiency expression remains challenging. We develop a system in human pluripotent stem cells (hPSCs) using CRISPR/Cas9 and SMASh technology, with which we can target endogenous proteins for precise dosage control in hPSCs and at multiple stages of neural differentiation. We also reveal FOXG1 dose-dependently affect the cellular constitution of human brain, with 60% mildly affect GABAergic interneuron development while 30% thresholds the production of MGE derived neurons. Abnormal interneuron differentiation accounts for various neurological defects such as epilepsy or seizures, which stimulates future innovative cures of FOXG1 syndrome. By means of its robustness and easiness, dosage-control of proteins in hPSCs and their derivatives will update the understanding and treatment of additional diseases caused by abnormal protein dosage.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Células-Tronco Pluripotentes/metabolismo , Animais , Diferenciação Celular , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Humanos , Interneurônios/citologia , Interneurônios/metabolismo , Masculino , Camundongos , Camundongos SCID , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Células-Tronco Pluripotentes/citologia , Ácido gama-Aminobutírico/metabolismo
17.
Dev Biol ; 448(1): 36-47, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30695685

RESUMO

Joubert syndrome (JBTS) is a predominantly autosomal recessive neurodevelopmental disorder that presents with characteristic malformations of the cerebellar vermis, superior cerebellar peduncles and midbrain in humans. Accompanying these malformations are a heterogeneous set of clinical symptoms, which frequently include deficits in motor and muscle function, such as hypotonia (low muscle tone) and ataxia (clumsiness). These symptoms are attributed to improper development of the hindbrain, but no direct evidence has been reported linking these in JBTS. Here, we describe muscle developmental defects in a mouse with a targeted deletion of the Abelson helper integration site 1 gene, Ahi1, one of the genes known to cause JBTS in humans. While FVB/NJ Ahi1-/- mice display no gross malformations of the cerebellum, deficits are observed in several measures of motor function, strength, and body development. Specifically, Ahi1-/- mice show delayed physical development, delays in surface reflex righting as neonates, and reductions in grip strength and spontaneous locomotor activity as adults. Additionally, Ahi1-/- mice showed evidence of muscle-specific contributions to this phenotype, such as reductions in 1) myoblast differentiation potential in vitro, 2) muscle desmin expression, and 3) overall muscle mass, myonuclear domain, and muscle fiber cross-sectional area. Together, these data suggest that loss of Ahi1 may cause abnormalities in the differentiation of myoblasts to mature muscle cells. Moreover, Ahi1 loss impacts muscle development directly, outside of any indirect impact of cerebellar malformations, revealing a novel myogenic cause for hypotonia in JBTS.


Assuntos
Anormalidades Múltiplas/embriologia , Diferenciação Celular , Cerebelo/anormalidades , Anormalidades do Olho/embriologia , Doenças Renais Císticas/embriologia , Desenvolvimento Muscular , Transtornos do Neurodesenvolvimento/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Animais , Cerebelo/embriologia , Cerebelo/patologia , Desmina/genética , Desmina/metabolismo , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Locomoção/genética , Camundongos , Camundongos Knockout , Força Muscular/genética , Mioblastos/metabolismo , Mioblastos/patologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Proteínas Proto-Oncogênicas/metabolismo , Reflexo de Endireitamento/genética , Retina/embriologia , Retina/patologia
18.
Nat Commun ; 10(1): 410, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679432

RESUMO

The contribution of de novo variants in severe intellectual disability (ID) has been extensively studied whereas the genetics of mild ID has been less characterized. To elucidate the genetics of milder ID we studied 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland. Using exome sequencing, we show that rare damaging variants in known ID genes are observed significantly more often in severe (27%) than in mild ID (13%) patients. We further observe a significant enrichment of functional variants in genes not yet associated with ID (OR: 2.1). We show that a common variant polygenic risk significantly contributes to ID. The heritability explained by polygenic risk score is the highest for educational attainment (EDU) in mild ID (2.2%) but lower for more severe ID (0.6%). Finally, we identify a Finland enriched homozygote variant in the CRADD ID associated gene.


Assuntos
Variações do Número de Cópias de DNA/genética , Variação Genética/genética , Genoma Humano/genética , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Proteína Adaptadora de Sinalização CRADD/genética , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/genética , Estudos de Coortes , Exoma , Feminino , Finlândia/epidemiologia , Estudos de Associação Genética , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Geografia , Homozigoto , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Herança Multifatorial , Mutação , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/genética , Patologia Molecular , Prevalência , Sequenciamento Completo do Exoma
19.
J Hum Genet ; 64(4): 313-322, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30655572

RESUMO

Casein kinase 2 (CK2) is a serine threonine kinase ubiquitously expressed in eukaryotic cells and involved in various cellular processes. In recent studies, de novo variants in CSNK2A1 and CSNK2B, which encode the subunits of CK2, have been identified in individuals with intellectual disability syndrome. In this study, we describe four patients with neurodevelopmental disorders possessing de novo variants in CSNK2A1 or CSNK2B. Using whole-exome sequencing, we detected two de novo variants in CSNK2A1 in two unrelated Japanese patients, a novel variant c.571C>T, p.(Arg191*) and a recurrent variant c.593A>G, p.(Lys198Arg), and two novel de novo variants in CSNK2B in Japanese and Malaysian patients, c.494A>G, p.(His165Arg) and c.533_534insGT, p.(Pro179Tyrfs*49), respectively. All four patients showed mild to profound intellectual disabilities, developmental delays, and various types of seizures. This and previous studies have found a total of 20 CSNK2A1 variants in 28 individuals with syndromic intellectual disability. The hotspot variant c.593A>G, p.(Lys198Arg) was found in eight of 28 patients. Meanwhile, only five CSNK2B variants were identified in five individuals with neurodevelopmental disorders. We reviewed the previous literature to verify the phenotypic spectrum of CSNK2A1- and CSNK2B-related syndromes.


Assuntos
Caseína Quinase II/genética , Deficiências do Desenvolvimento/genética , Convulsões/genética , Adolescente , Criança , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Linhagem , Convulsões/complicações , Convulsões/fisiopatologia , Sequenciamento Completo do Exoma
20.
J Hum Genet ; 64(4): 271-280, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30670789

RESUMO

A decade ago, we described novel de novo submicroscopic deletions of chromosome 14q11.2 in three children with developmental delay, cognitive impairment, and similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip, and auricular anomalies. We suggested that this constituted a new multiple congenital anomaly-intellectual disability syndrome due to defects in CHD8 and/or SUPT16H. The three patients in our original cohort were between 2 years and 3 years of age at the time. Here we present a fourth patient and clinical updates on our previous patients. To document the longitudinal course more fully, we integrate published reports of other patients and describe genotype-phenotype correlations among them. Children with the disorder present with developmental delay, intellectual disability, and/or autism spectrum disorder in addition to characteristic facies. Gastrointestinal and sleep problems are notable. The identification of multiple patients with the same genetic defect and characteristic clinical phenotype, confirms our suggestion that this is a syndromic disorder caused by haploinsufficiency or heterozygous loss of function of CHD8.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Facies , Feminino , Haploinsuficiência/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/genética , Megalencefalia/fisiopatologia , Transtornos do Neurodesenvolvimento/patologia
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