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1.
Hum Mol Genet ; 32(9): 1497-1510, 2023 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-36579832

RESUMO

TBR1 is a neuron-specific transcription factor involved in brain development and implicated in a neurodevelopmental disorder (NDD) combining features of autism spectrum disorder (ASD), intellectual disability (ID) and speech delay. TBR1 has been previously shown to interact with a small number of transcription factors and co-factors also involved in NDDs (including CASK, FOXP1/2/4 and BCL11A), suggesting that the wider TBR1 interactome may have a significant bearing on normal and abnormal brain development. Here, we have identified approximately 250 putative TBR1-interaction partners by affinity purification coupled to mass spectrometry. As well as known TBR1-interactors such as CASK, the identified partners include transcription factors and chromatin modifiers, along with ASD- and ID-related proteins. Five interaction candidates were independently validated using bioluminescence resonance energy transfer assays. We went on to test the interaction of these candidates with TBR1 protein variants implicated in cases of NDD. The assays uncovered disturbed interactions for NDD-associated variants and identified two distinct protein-binding domains of TBR1 that have essential roles in protein-protein interaction.


Assuntos
Transtornos do Neurodesenvolvimento , Proteínas com Domínio T , Humanos , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Ligação Proteica/genética , Ligação Proteica/fisiologia , Proteínas/genética , Proteínas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
2.
Am J Hum Genet ; 108(2): 346-356, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33513338

RESUMO

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.


Assuntos
Proteínas de Ligação à Região de Interação com a Matriz/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Cromatina/metabolismo , Feminino , Estudos de Associação Genética , Haploinsuficiência , Humanos , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/química , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Modelos Moleculares , Mutação de Sentido Incorreto , Ligação Proteica , Domínios Proteicos , Transcrição Gênica
3.
EMBO Rep ; 22(8): e52803, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34260143

RESUMO

The discovery of the FOXP2 transcription factor, and its implication in a rare severe human speech and language disorder, has led to two decades of empirical studies focused on uncovering its roles in the brain using a range of in vitro and in vivo methods. Here, we discuss what we have learned about the regulation of FOXP2, its downstream effectors, and its modes of action as a transcription factor in brain development and function, providing an integrated overview of what is currently known about the critical molecular networks.


Assuntos
Encéfalo , Fatores de Transcrição Forkhead , Encéfalo/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Humanos , Fala
4.
Genet Med ; 24(6): 1283-1296, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35346573

RESUMO

PURPOSE: Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed. METHODS: We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome. RESULTS: Computational facial and Human Phenotype Ontology-based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted. CONCLUSION: Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease.


Assuntos
DNA Helicases , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase , Transtornos do Neurodesenvolvimento , DNA Helicases/genética , Heterozigoto , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Síndrome
5.
Cell Mol Life Sci ; 78(7): 3503-3524, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33340069

RESUMO

Members of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with multiple neurodevelopmental disorders, although their exact roles in disease remain unclear. For example, nuclear receptor coactivator 7 (NCOA7) has been associated with autism, although almost nothing is known regarding the mode-of-action of this TLDc protein in the nervous system. Here we investigated the molecular function of NCOA7 in neurons and generated a novel mouse model to determine the consequences of deleting this locus in vivo. We show that NCOA7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase in the brain and demonstrate that this protein is required for normal assembly and activity of this critical proton pump. Neurons lacking Ncoa7 exhibit altered development alongside defective lysosomal formation and function; accordingly, Ncoa7 deletion animals exhibited abnormal neuronal patterning defects and a reduced expression of lysosomal markers. Furthermore, behavioural assessment revealed anxiety and social defects in mice lacking Ncoa7. In summary, we demonstrate that NCOA7 is an important V-ATPase regulatory protein in the brain, modulating lysosomal function, neuronal connectivity and behaviour; thus our study reveals a molecular mechanism controlling endolysosomal homeostasis that is essential for neurodevelopment.


Assuntos
Comportamento Animal , Modelos Animais de Doenças , Transtornos do Neurodesenvolvimento/patologia , Neurônios/patologia , Coativadores de Receptor Nuclear/fisiologia , Estresse Oxidativo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Animais , Endossomos/metabolismo , Feminino , Lisossomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/metabolismo , Neurônios/metabolismo , ATPases Vacuolares Próton-Translocadoras/genética
6.
Genet Med ; 23(3): 534-542, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33110267

RESUMO

PURPOSE: Heterozygous pathogenic variants in various FOXP genes cause specific developmental disorders. The phenotype associated with heterozygous variants in FOXP4 has not been previously described. METHODS: We assembled a cohort of eight individuals with heterozygous and mostly de novo variants in FOXP4: seven individuals with six different missense variants and one individual with a frameshift variant. We collected clinical data to delineate the phenotypic spectrum, and used in silico analyses and functional cell-based assays to assess pathogenicity of the variants. RESULTS: We collected clinical data for six individuals: five individuals with a missense variant in the forkhead box DNA-binding domain of FOXP4, and one individual with a truncating variant. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia, cervical spine abnormalities, and ptosis. Luciferase assays showed loss-of-function effects for all these variants, and aberrant subcellular localization patterns were seen in a subset. The remaining two missense variants were located outside the functional domains of FOXP4, and showed transcriptional repressor capacities and localization patterns similar to the wild-type protein. CONCLUSION: Collectively, our findings show that heterozygous loss-of-function variants in FOXP4 are associated with an autosomal dominant neurodevelopmental disorder with speech/language delays, growth defects, and variable congenital abnormalities.


Assuntos
Anormalidades Múltiplas , Deficiência Intelectual , Transtornos do Desenvolvimento da Linguagem , Criança , Deficiências do Desenvolvimento/genética , Fatores de Transcrição Forkhead/genética , Heterozigoto , Humanos , Transtornos do Desenvolvimento da Linguagem/genética , Mutação de Sentido Incorreto , Fala
7.
HGG Adv ; 4(1): 100157, 2023 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-36408368

RESUMO

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features included abnormal growth parameters (n = 7), heart anomalies (n = 2), and hearing loss (n = 2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization, and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders.


Assuntos
Transtorno do Espectro Autista , Proteínas de Drosophila , Transtornos do Desenvolvimento da Linguagem , Transtornos do Neurodesenvolvimento , Animais , Humanos , Transtorno do Espectro Autista/genética , Drosophila melanogaster/genética , Transtornos do Neurodesenvolvimento/genética , Análise por Conglomerados , Cromatina , Peptídeos e Proteínas de Sinalização Intracelular/genética , Histona-Lisina N-Metiltransferase/genética , Proteínas de Drosophila/genética
8.
Nat Genet ; 55(9): 1598-1607, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37550531

RESUMO

Several molecular and phenotypic algorithms exist that establish genotype-phenotype correlations, including facial recognition tools. However, no unified framework that investigates both facial data and other phenotypic data directly from individuals exists. We developed PhenoScore: an open-source, artificial intelligence-based phenomics framework, combining facial recognition technology with Human Phenotype Ontology data analysis to quantify phenotypic similarity. Here we show PhenoScore's ability to recognize distinct phenotypic entities by establishing recognizable phenotypes for 37 of 40 investigated syndromes against clinical features observed in individuals with other neurodevelopmental disorders and show it is an improvement on existing approaches. PhenoScore provides predictions for individuals with variants of unknown significance and enables sophisticated genotype-phenotype studies by testing hypotheses on possible phenotypic (sub)groups. PhenoScore confirmed previously known phenotypic subgroups caused by variants in the same gene for SATB1, SETBP1 and DEAF1 and provides objective clinical evidence for two distinct ADNP-related phenotypes, already established functionally.


Assuntos
Inteligência Artificial , Proteínas de Ligação à Região de Interação com a Matriz , Humanos , Fenótipo , Algoritmos , Aprendizado de Máquina , Variação Biológica da População , Proteínas de Ligação a DNA , Fatores de Transcrição
9.
Curr Opin Genet Dev ; 65: 103-111, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32622339

RESUMO

Rare genetic variants that disrupt speech development provide entry points for deciphering the neurobiological foundations of key human capacities. The value of this approach is illustrated by FOXP2, a transcription factor gene that was implicated in speech apraxia, and subsequently investigated using human cell-based systems and animal models. Advances in next-generation sequencing, coupled to de novo paradigms, facilitated discovery of etiological variants in additional genes in speech disorder cohorts. As for other neurodevelopmental syndromes, gene-driven studies show blurring of boundaries between diagnostic categories, with some risk genes shared across speech disorders, intellectual disability and autism. Convergent evidence hints at involvement of regulatory genes co-expressed in early human brain development, suggesting that etiological pathways could be amenable for investigation in emerging neural models such as cerebral organoids.


Assuntos
Regulação da Expressão Gênica , Marcadores Genéticos , Predisposição Genética para Doença , Genoma Humano , Distúrbios da Fala/genética , Distúrbios da Fala/patologia , Animais , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
10.
Philos Trans R Soc Lond B Biol Sci ; 374(1787): 20190026, 2019 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-31630655

RESUMO

Synaesthesia is a neurological phenomenon affecting perception, where triggering stimuli (e.g. letters and numbers) elicit unusual secondary sensory experiences (e.g. colours). Family-based studies point to a role for genetic factors in the development of this trait. However, the contributions of common genomic variation to synaesthesia have not yet been investigated. Here, we present the SynGenes cohort, the largest genotyped collection of unrelated people with grapheme-colour synaesthesia (n = 723). Synaesthesia has been associated with a range of other neuropsychological traits, including enhanced memory and mental imagery, as well as greater sensory sensitivity. Motivated by the prior literature on putative trait overlaps, we investigated polygenic scores derived from published genome-wide scans of schizophrenia and autism spectrum disorder (ASD), comparing our SynGenes cohort to 2181 non-synaesthetic controls. We found a very slight association between schizophrenia polygenic scores and synaesthesia (Nagelkerke's R2 = 0.0047, empirical p = 0.0027) and no significant association for scores related to ASD (Nagelkerke's R2 = 0.00092, empirical p = 0.54) or body mass index (R2 = 0.00058, empirical p = 0.60), included as a negative control. As sample sizes for studying common genomic variation continue to increase, genetic investigations of the kind reported here may yield novel insights into the shared biology between synaesthesia and other traits, to complement findings from neuropsychology and brain imaging. This article is part of a discussion meeting issue 'Bridging senses: novel insights from synaesthesia'.


Assuntos
Sinestesia/genética , Sinestesia/psicologia , Adolescente , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/psicologia , Criança , Pré-Escolar , Estudos de Coortes , Percepção de Cores , Feminino , Humanos , Imaginação , Masculino , Memória , Herança Multifatorial , Testes Neuropsicológicos
11.
Sci Rep ; 8(1): 14279, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30250039

RESUMO

Recurrent de novo variants in the TBR1 transcription factor are implicated in the etiology of sporadic autism spectrum disorders (ASD). Disruptions include missense variants located in the T-box DNA-binding domain and previous work has demonstrated that they disrupt TBR1 protein function. Recent screens of thousands of simplex families with sporadic ASD cases uncovered additional T-box variants in TBR1 but their etiological relevance is unclear. We performed detailed functional analyses of de novo missense TBR1 variants found in the T-box of ASD cases, assessing many aspects of protein function, including subcellular localization, transcriptional activity and protein-interactions. Only two of the three tested variants severely disrupted TBR1 protein function, despite in silico predictions that all would be deleterious. Furthermore, we characterized a putative interaction with BCL11A, a transcription factor that was recently implicated in a neurodevelopmental syndrome involving developmental delay and language deficits. Our findings enhance understanding of molecular functions of TBR1, as well as highlighting the importance of functional testing of variants that emerge from next-generation sequencing, to decipher their contributions to neurodevelopmental disorders like ASD.


Assuntos
Transtorno do Espectro Autista/genética , Deficiências do Desenvolvimento/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas com Domínio T/genética , Transtorno do Espectro Autista/fisiopatologia , Deficiências do Desenvolvimento/fisiopatologia , Exoma/genética , Regulação da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Conformação Proteica , Proteínas com Domínio T/química , Sequenciamento do Exoma
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