3 recherche sur le mot-clé 'Transcription Factors/genetics'

Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice / Markus WÖHR in Molecular Autism, 13 (2022)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 19 p. Titre : Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice Type de document : Texte imprimé et/ou numérique Auteurs : Markus WÖHR, Auteur ; Wendy M. FONG, Auteur ; Justyna A. JANAS, Auteur ; Moritz MALL, Auteur ; Christian THOME, Auteur ; Madhuri VANGIPURAM, Auteur ; Lingjun MENG, Auteur ; Thomas C. SÜDHOF, Auteur ; Marius WERNIG, Auteur Article en page(s) : 19 p. Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics  Behavior, Animal/physiology  Haploinsufficiency  Mice  Nerve Tissue Proteins/genetics  Obesity  Transcription Factors/genetics  Autism  Social behavior  Transcription factor  Ultrasonic vocalization Index. décimale : PER Périodiques Résumé : BACKGROUND: The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. METHODS: Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. RESULTS: Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. LIMITATIONS: In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. CONCLUSIONS: Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome. En ligne : http://dx.doi.org/10.1186/s13229-022-00497-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477 [article] Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice [Texte imprimé et/ou numérique] / Markus WÖHR, Auteur ; Wendy M. FONG, Auteur ; Justyna A. JANAS, Auteur ; Moritz MALL, Auteur ; Christian THOME, Auteur ; Madhuri VANGIPURAM, Auteur ; Lingjun MENG, Auteur ; Thomas C. SÜDHOF, Auteur ; Marius WERNIG, Auteur . - 19 p. Langues : Anglais (eng) in Molecular Autism > 13 (2022) . - 19 p. Mots-clés : Animals  Autism Spectrum Disorder/genetics  Behavior, Animal/physiology  Haploinsufficiency  Mice  Nerve Tissue Proteins/genetics  Obesity  Transcription Factors/genetics  Autism  Social behavior  Transcription factor  Ultrasonic vocalization Index. décimale : PER Périodiques Résumé : BACKGROUND: The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. METHODS: Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. RESULTS: Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. LIMITATIONS: In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. CONCLUSIONS: Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome. En ligne : http://dx.doi.org/10.1186/s13229-022-00497-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477

Novel Variants of the SMARCA4 Gene Associated with Autistic Features Rather Than Typical Coffin-Siris Syndrome in Eight Chinese Pediatric Patients / Yanyan QIAN in Journal of Autism and Developmental Disorders, 52-11 (November 2022)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 52-11 (November 2022) . - p.5033-5041 Titre : Novel Variants of the SMARCA4 Gene Associated with Autistic Features Rather Than Typical Coffin-Siris Syndrome in Eight Chinese Pediatric Patients Type de document : Texte imprimé et/ou numérique Auteurs : Yanyan QIAN, Auteur ; Yuanfeng ZHOU, Auteur ; Bingbing WU, Auteur ; Huiyao CHEN, Auteur ; Suzhen XU, Auteur ; Yao WANG, Auteur ; Ping ZHANG, Auteur ; Gang LI, Auteur ; Qiong XU, Auteur ; Wenhao ZHOU, Auteur ; Xiu XU, Auteur ; Huijun WANG, Auteur Article en page(s) : p.5033-5041 Langues : Anglais (eng) Mots-clés : Abnormalities, Multiple  Autism Spectrum Disorder  Autistic Disorder/genetics  China  Chromatin  DNA Helicases/genetics  Face/abnormalities  Hand Deformities, Congenital  Humans  Intellectual Disability/genetics  Micrognathism  Neck/abnormalities  Nuclear Proteins/genetics  Transcription Factors/genetics  Autism spectrum disorder  Coffin-Siris syndrome  Neurodevelopmental-related disorders  Phenotype  Smarca4 Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASDs) are a group of neurodevelopmental-related disorders with a high genetic risk. Recently, chromatin remodeling factors have been found to be related to ASDs. SMARCA4 is such a catalytic subunit of the chromatin-remodeling complex. In this report, we identified seven novel missense variants in the SMARCA4 gene from eight pediatric patients. All eight patients had moderate to severe intellectual disability, and seven showed autistic/likely autistic features. Compared with the patients reported in the literature, our patients were less likely to show craniofacial or finger/toe anomalies. Our findings further supported that SMARCA4 is associated with ASDs. We suggest that individuals with the abovementioned phenotypes should consider genetic testing. En ligne : http://dx.doi.org/10.1007/s10803-021-05365-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=489 [article] Novel Variants of the SMARCA4 Gene Associated with Autistic Features Rather Than Typical Coffin-Siris Syndrome in Eight Chinese Pediatric Patients [Texte imprimé et/ou numérique] / Yanyan QIAN, Auteur ; Yuanfeng ZHOU, Auteur ; Bingbing WU, Auteur ; Huiyao CHEN, Auteur ; Suzhen XU, Auteur ; Yao WANG, Auteur ; Ping ZHANG, Auteur ; Gang LI, Auteur ; Qiong XU, Auteur ; Wenhao ZHOU, Auteur ; Xiu XU, Auteur ; Huijun WANG, Auteur . - p.5033-5041. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 52-11 (November 2022) . - p.5033-5041 Mots-clés : Abnormalities, Multiple  Autism Spectrum Disorder  Autistic Disorder/genetics  China  Chromatin  DNA Helicases/genetics  Face/abnormalities  Hand Deformities, Congenital  Humans  Intellectual Disability/genetics  Micrognathism  Neck/abnormalities  Nuclear Proteins/genetics  Transcription Factors/genetics  Autism spectrum disorder  Coffin-Siris syndrome  Neurodevelopmental-related disorders  Phenotype  Smarca4 Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASDs) are a group of neurodevelopmental-related disorders with a high genetic risk. Recently, chromatin remodeling factors have been found to be related to ASDs. SMARCA4 is such a catalytic subunit of the chromatin-remodeling complex. In this report, we identified seven novel missense variants in the SMARCA4 gene from eight pediatric patients. All eight patients had moderate to severe intellectual disability, and seven showed autistic/likely autistic features. Compared with the patients reported in the literature, our patients were less likely to show craniofacial or finger/toe anomalies. Our findings further supported that SMARCA4 is associated with ASDs. We suggest that individuals with the abovementioned phenotypes should consider genetic testing. En ligne : http://dx.doi.org/10.1007/s10803-021-05365-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=489

A systematic variant annotation approach for ranking genes associated with autism spectrum disorders / E. LARSEN in Molecular Autism, 7 (2016)  

Public ISBD [article]  inMolecular Autism > 7 (2016) . - 44p. Titre : A systematic variant annotation approach for ranking genes associated with autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : E. LARSEN, Auteur ; I. MENASHE, Auteur ; M. N. ZIATS, Auteur ; W. PEREANU, Auteur ; A. PACKER, Auteur ; Sharmila BANERJEE-BASU, Auteur Article en page(s) : 44p. Langues : Anglais (eng) Mots-clés : Algorithms  Autism Spectrum Disorder/genetics/physiopathology  DNA-Binding Proteins/genetics  Databases, Genetic  Datasets as Topic  Gene Expression  Genetic Predisposition to Disease  Genetic Variation  Homeodomain Proteins/genetics  Humans  Molecular Sequence Annotation  Nerve Tissue Proteins/genetics  Research Design  Transcription Factors/genetics  Autistic disorder  Autosomal recessive  Common variants  Genetic variation  Rare variants Index. décimale : PER Périodiques Résumé : BACKGROUND: The search for genetic factors underlying autism spectrum disorders (ASD) has led to the identification of hundreds of genes containing thousands of variants that differ in mode of inheritance, effect size, frequency, and function. A major challenge involves assessing the collective evidence in an unbiased, systematic manner for their functional relevance. METHODS: Here, we describe a scoring algorithm for prioritization of candidate genes based on the cumulative strength of evidence for each ASD-associated variant cataloged in AutDB (also known as SFARI Gene). We retrieved data from 889 publications to generate a dataset of 2187 rare and 711 common variants distributed across 461 genes implicated in ASD. Each individual variant was manually annotated with multiple attributes extracted from the original report, followed by score assignment using a set of standardized parameters yielding a single score for each gene. RESULTS: There was a wide variation in scores; SHANK3, CHD8, and ADNP had distinctly higher scores than all other genes in the dataset. Our gene scores were significantly correlated with other recently published rankings of ASD genes (RSpearman = 0.40-0.63; p< 0.0001), providing support for our scoring algorithm. CONCLUSIONS: This new resource, which is freely available, for the first time aggregates on one-platform variants identified from various study types (simplex, multiplex, multigenerational, and consanguineous families), from both common and rare variants, and also incorporates their putative functional consequences to arrive at a genetically and biologically driven ranking scheme. This work represents a major step in moving from simply cataloging autism variants to using data-driven approaches to gain insight into their significance. En ligne : http://dx.doi.org/10.1186/s13229-016-0103-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 [article] A systematic variant annotation approach for ranking genes associated with autism spectrum disorders [Texte imprimé et/ou numérique] / E. LARSEN, Auteur ; I. MENASHE, Auteur ; M. N. ZIATS, Auteur ; W. PEREANU, Auteur ; A. PACKER, Auteur ; Sharmila BANERJEE-BASU, Auteur . - 44p. Langues : Anglais (eng) in Molecular Autism > 7 (2016) . - 44p. Mots-clés : Algorithms  Autism Spectrum Disorder/genetics/physiopathology  DNA-Binding Proteins/genetics  Databases, Genetic  Datasets as Topic  Gene Expression  Genetic Predisposition to Disease  Genetic Variation  Homeodomain Proteins/genetics  Humans  Molecular Sequence Annotation  Nerve Tissue Proteins/genetics  Research Design  Transcription Factors/genetics  Autistic disorder  Autosomal recessive  Common variants  Genetic variation  Rare variants Index. décimale : PER Périodiques Résumé : BACKGROUND: The search for genetic factors underlying autism spectrum disorders (ASD) has led to the identification of hundreds of genes containing thousands of variants that differ in mode of inheritance, effect size, frequency, and function. A major challenge involves assessing the collective evidence in an unbiased, systematic manner for their functional relevance. METHODS: Here, we describe a scoring algorithm for prioritization of candidate genes based on the cumulative strength of evidence for each ASD-associated variant cataloged in AutDB (also known as SFARI Gene). We retrieved data from 889 publications to generate a dataset of 2187 rare and 711 common variants distributed across 461 genes implicated in ASD. Each individual variant was manually annotated with multiple attributes extracted from the original report, followed by score assignment using a set of standardized parameters yielding a single score for each gene. RESULTS: There was a wide variation in scores; SHANK3, CHD8, and ADNP had distinctly higher scores than all other genes in the dataset. Our gene scores were significantly correlated with other recently published rankings of ASD genes (RSpearman = 0.40-0.63; p< 0.0001), providing support for our scoring algorithm. CONCLUSIONS: This new resource, which is freely available, for the first time aggregates on one-platform variants identified from various study types (simplex, multiplex, multigenerational, and consanguineous families), from both common and rare variants, and also incorporates their putative functional consequences to arrive at a genetically and biologically driven ranking scheme. This work represents a major step in moving from simply cataloging autism variants to using data-driven approaches to gain insight into their significance. En ligne : http://dx.doi.org/10.1186/s13229-016-0103-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328