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1.
Hum Mol Genet ; 29(9): 1498-1519, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32313931

RESUMO

Gtf2ird1 and Gtf2i are two transcription factors (TFs) among the 28 genes deleted in Williams syndrome, and prior mouse models of each TF show behavioral phenotypes. Here we identify their genomic binding sites in the developing brain and test for additive effects of their mutation on transcription and behavior. GTF2IRD1 binding targets were enriched for transcriptional and chromatin regulators and mediators of ubiquitination. GTF2I targets were enriched for signal transduction proteins, including regulators of phosphorylation and WNT. Both TFs are highly enriched at promoters, strongly overlap CTCF binding and topological associating domain boundaries and moderately overlap each other, suggesting epistatic effects. Shared TF targets are enriched for reactive oxygen species-responsive genes, synaptic proteins and transcription regulators such as chromatin modifiers, including a significant number of highly constrained genes and known ASD genes. We next used single and double mutants to test whether mutating both TFs will modify transcriptional and behavioral phenotypes of single Gtf2ird1 mutants, though with the caveat that our Gtf2ird1 mutants, like others previously reported, do produce low levels of a truncated protein product. Despite little difference in DNA binding and transcriptome-wide expression, homozygous Gtf2ird1 mutation caused balance, marble burying and conditioned fear phenotypes. However, mutating Gtf2i in addition to Gtf2ird1 did not further modify transcriptomic or most behavioral phenotypes, suggesting Gtf2ird1 mutation alone was sufficient for the observed phenotypes.


Assuntos
Fator de Ligação a CCCTC/genética , Proteínas Musculares/genética , Transativadores/genética , Fatores de Transcrição TFII/genética , Síndrome de Williams/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Sistemas CRISPR-Cas/genética , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Desenvolvimento Embrionário/genética , Edição de Genes , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Camundongos , Transcrição Gênica/genética , Síndrome de Williams/patologia
2.
Stem Cell Reports ; 14(4): 541-550, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32243842

RESUMO

Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by a spectrum of distinct germline NF1 gene mutations, traditionally viewed as equivalent loss-of-function alleles. To specifically address the issue of mutational equivalency in a disease with considerable clinical heterogeneity, we engineered seven isogenic human induced pluripotent stem cell lines, each with a different NF1 patient NF1 mutation, to identify potential differential effects of NF1 mutations on human central nervous system cells and tissues. Although all mutations increased proliferation and RAS activity in 2D neural progenitor cells (NPCs) and astrocytes, we observed striking differences between NF1 mutations on 2D NPC dopamine levels, and 3D NPC proliferation, apoptosis, and neuronal differentiation in developing cerebral organoids. Together, these findings demonstrate differential effects of NF1 gene mutations at the cellular and tissue levels, suggesting that the germline NF1 gene mutation is one factor that underlies clinical variability.


Assuntos
Encéfalo/patologia , Genes da Neurofibromatose 1 , Células-Tronco Pluripotentes Induzidas/patologia , Mutação/genética , Neurônios/patologia , Organoides/patologia , Animais , Apoptose , Astrócitos/patologia , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos Mutantes , Neurogênese , Neurônios/metabolismo , Proteínas ras/metabolismo
3.
Mol Genet Genomic Med ; 6(5): 749-765, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30008175

RESUMO

BACKGROUND: Large, multigenic deletions at chromosome 7q11.23 result in a highly penetrant constellation of physical and behavioral symptoms known as Williams-Beuren syndrome (WS). Of particular interest is the unusual social-cognitive profile evidenced by deficits in social cognition and communication reminiscent of autism spectrum disorders (ASD) that are juxtaposed with normal or even relatively enhanced social motivation. Interestingly, duplications in the same region also result in ASD-like phenotypes as well as social phobias. Thus, the region clearly regulates human social motivation and behavior, yet the relevant gene(s) have not been definitively identified. METHOD: Here, we deeply phenotyped 85 individuals with WS and used exome sequencing to analyze common and rare variation for association with the remaining variance in social behavior as assessed by the Social Responsiveness Scale. RESULTS: We replicated the previously reported unusual juxtaposition of behavioral symptoms in this new patient collection, but we did not find any new alleles of large effect in the targeted analysis of the remaining copy of genes in the Williams syndrome critical region. However, we report on two nominally significant SNPs in two genes that have been implicated in the cognitive and social phenotypes of Williams syndrome, BAZ1B and GTF2IRD1. Secondary discovery driven explorations focusing on known ASD genes and an exome wide scan do not highlight any variants of a large effect. CONCLUSIONS: Whole exome sequencing of 85 individuals with WS did not support the hypothesis that there are variants of large effect within the remaining Williams syndrome critical region that contribute to the social phenotype. This deeply phenotyped and genotyped patient cohort with a defined mutation provides the opportunity for similar analyses focusing on noncoding variation and/or other phenotypic domains.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Sequenciamento do Exoma , Proteínas Musculares/genética , Proteínas Nucleares/genética , Comportamento Social , Transativadores/genética , Fatores de Transcrição/genética , Síndrome de Williams/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Exoma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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