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Auteur A. S. BASSETT |
Documents disponibles écrits par cet auteur (2)
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Comparative mapping of the 22q11.2 deletion region and the potential of simple model organisms / A. GUNA in Journal of Neurodevelopmental Disorders, 7-1 (December 2015)
[article]
Titre : Comparative mapping of the 22q11.2 deletion region and the potential of simple model organisms Type de document : Texte imprimé et/ou numérique Auteurs : A. GUNA, Auteur ; N. J. BUTCHER, Auteur ; A. S. BASSETT, Auteur Article en page(s) : p.18 Langues : Anglais (eng) Mots-clés : Animal models Dgcr8 DiGeorge syndrome Homolog Homology Prodh Slc25a1 Tbx1 Velocardiofacial syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is the most common micro-deletion syndrome. The associated 22q11.2 deletion conveys the strongest known molecular risk for schizophrenia. Neurodevelopmental phenotypes, including intellectual disability, are also prominent though variable in severity. Other developmental features include congenital cardiac and craniofacial anomalies. Whereas existing mouse models have been helpful in determining the role of some genes overlapped by the hemizygous 22q11.2 deletion in phenotypic expression, much remains unknown. Simple model organisms remain largely unexploited in exploring these genotype-phenotype relationships. METHODS: We first developed a comprehensive map of the human 22q11.2 deletion region, delineating gene content, and brain expression. To identify putative orthologs, standard methods were used to interrogate the proteomes of the zebrafish (D. rerio), fruit fly (D. melanogaster), and worm (C. elegans), in addition to the mouse. Spatial locations of conserved homologues were mapped to examine syntenic relationships. We systematically cataloged available knockout and knockdown models of all conserved genes across these organisms, including a comprehensive review of associated phenotypes. RESULTS: There are 90 genes overlapped by the typical 2.5 Mb deletion 22q11.2 region. Of the 46 protein-coding genes, 41 (89.1 %) have documented expression in the human brain. Identified homologues in the zebrafish (n = 37, 80.4 %) were comparable to those in the mouse (n = 40, 86.9 %) and included some conserved gene cluster structures. There were 22 (47.8 %) putative homologues in the fruit fly and 17 (37.0 %) in the worm involving multiple chromosomes. Individual gene knockdown mutants were available for the simple model organisms, but not for mouse. Although phenotypic data were relatively limited for knockout and knockdown models of the 17 genes conserved across all species, there was some evidence for roles in neurodevelopmental phenotypes, including four of the six mitochondrial genes in the 22q11.2 deletion region. CONCLUSIONS: Simple model organisms represent a powerful but underutilized means of investigating the molecular mechanisms underlying the elevated risk for neurodevelopmental disorders in 22q11.2DS. This comparative multi-species study provides novel resources and support for the potential utility of non-mouse models in expression studies and high-throughput drug screening. The approach has implications for other recurrent copy number variations associated with neurodevelopmental phenotypes. En ligne : http://dx.doi.org/10.1186/s11689-015-9113-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=347
in Journal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.18[article] Comparative mapping of the 22q11.2 deletion region and the potential of simple model organisms [Texte imprimé et/ou numérique] / A. GUNA, Auteur ; N. J. BUTCHER, Auteur ; A. S. BASSETT, Auteur . - p.18.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.18
Mots-clés : Animal models Dgcr8 DiGeorge syndrome Homolog Homology Prodh Slc25a1 Tbx1 Velocardiofacial syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is the most common micro-deletion syndrome. The associated 22q11.2 deletion conveys the strongest known molecular risk for schizophrenia. Neurodevelopmental phenotypes, including intellectual disability, are also prominent though variable in severity. Other developmental features include congenital cardiac and craniofacial anomalies. Whereas existing mouse models have been helpful in determining the role of some genes overlapped by the hemizygous 22q11.2 deletion in phenotypic expression, much remains unknown. Simple model organisms remain largely unexploited in exploring these genotype-phenotype relationships. METHODS: We first developed a comprehensive map of the human 22q11.2 deletion region, delineating gene content, and brain expression. To identify putative orthologs, standard methods were used to interrogate the proteomes of the zebrafish (D. rerio), fruit fly (D. melanogaster), and worm (C. elegans), in addition to the mouse. Spatial locations of conserved homologues were mapped to examine syntenic relationships. We systematically cataloged available knockout and knockdown models of all conserved genes across these organisms, including a comprehensive review of associated phenotypes. RESULTS: There are 90 genes overlapped by the typical 2.5 Mb deletion 22q11.2 region. Of the 46 protein-coding genes, 41 (89.1 %) have documented expression in the human brain. Identified homologues in the zebrafish (n = 37, 80.4 %) were comparable to those in the mouse (n = 40, 86.9 %) and included some conserved gene cluster structures. There were 22 (47.8 %) putative homologues in the fruit fly and 17 (37.0 %) in the worm involving multiple chromosomes. Individual gene knockdown mutants were available for the simple model organisms, but not for mouse. Although phenotypic data were relatively limited for knockout and knockdown models of the 17 genes conserved across all species, there was some evidence for roles in neurodevelopmental phenotypes, including four of the six mitochondrial genes in the 22q11.2 deletion region. CONCLUSIONS: Simple model organisms represent a powerful but underutilized means of investigating the molecular mechanisms underlying the elevated risk for neurodevelopmental disorders in 22q11.2DS. This comparative multi-species study provides novel resources and support for the potential utility of non-mouse models in expression studies and high-throughput drug screening. The approach has implications for other recurrent copy number variations associated with neurodevelopmental phenotypes. En ligne : http://dx.doi.org/10.1186/s11689-015-9113-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=347 Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders / G. COSTAIN in Journal of Neurodevelopmental Disorders, 11-1 (December 2019)
[article]
Titre : Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders Type de document : Texte imprimé et/ou numérique Auteurs : G. COSTAIN, Auteur ; S. WALKER, Auteur ; B. ARGIROPOULOS, Auteur ; D. A. BARIBEAU, Auteur ; A. S. BASSETT, Auteur ; E. BOOT, Auteur ; Koenraad DEVRIENDT, Auteur ; B. KELLAM, Auteur ; C. R. MARSHALL, Auteur ; A. PRASAD, Auteur ; M. A. SERRANO, Auteur ; D. J. STAVROPOULOS, Auteur ; H. TWEDE, Auteur ; J. R. VERMEESCH, Auteur ; J. A. S. VORSTMAN, Auteur ; Stephen SCHERER, Auteur Article en page(s) : 3 p. Langues : Anglais (eng) Mots-clés : Adhd Autism Copy number variation Dmxl2 Grik5 Genome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Ultra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs. METHODS: We performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive of a NDD. CNVs and sequence-level variants were identified and further investigated in disease and control databases. RESULTS: We identified a novel 252-kb deletion at 15q21 that overlaps the synaptic gene DMXL2 and the gene GLDN. The microdeletion segregated in NDD-affected individuals. Additional rare inherited and de novo sequence-level variants were found that may also be involved, including a missense change in GRIK5. Multiple CNVs and loss-of-function sequence variants affecting DMXL2 were discovered in additional unrelated individuals with a range of NDDs. CONCLUSIONS: Disruption of DMXL2 may predispose to NDDs including autism spectrum disorder. The robust interpretation of private variants requires a multifaceted approach that incorporates multigenerational pedigrees and genome-wide and population-scale data. En ligne : http://dx.doi.org/10.1186/s11689-019-9263-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=386
in Journal of Neurodevelopmental Disorders > 11-1 (December 2019) . - 3 p.[article] Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders [Texte imprimé et/ou numérique] / G. COSTAIN, Auteur ; S. WALKER, Auteur ; B. ARGIROPOULOS, Auteur ; D. A. BARIBEAU, Auteur ; A. S. BASSETT, Auteur ; E. BOOT, Auteur ; Koenraad DEVRIENDT, Auteur ; B. KELLAM, Auteur ; C. R. MARSHALL, Auteur ; A. PRASAD, Auteur ; M. A. SERRANO, Auteur ; D. J. STAVROPOULOS, Auteur ; H. TWEDE, Auteur ; J. R. VERMEESCH, Auteur ; J. A. S. VORSTMAN, Auteur ; Stephen SCHERER, Auteur . - 3 p.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 11-1 (December 2019) . - 3 p.
Mots-clés : Adhd Autism Copy number variation Dmxl2 Grik5 Genome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Ultra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs. METHODS: We performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive of a NDD. CNVs and sequence-level variants were identified and further investigated in disease and control databases. RESULTS: We identified a novel 252-kb deletion at 15q21 that overlaps the synaptic gene DMXL2 and the gene GLDN. The microdeletion segregated in NDD-affected individuals. Additional rare inherited and de novo sequence-level variants were found that may also be involved, including a missense change in GRIK5. Multiple CNVs and loss-of-function sequence variants affecting DMXL2 were discovered in additional unrelated individuals with a range of NDDs. CONCLUSIONS: Disruption of DMXL2 may predispose to NDDs including autism spectrum disorder. The robust interpretation of private variants requires a multifaceted approach that incorporates multigenerational pedigrees and genome-wide and population-scale data. En ligne : http://dx.doi.org/10.1186/s11689-019-9263-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=386