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Clinical phenotype of ASD-associated DYRK1A haploinsufficiency / R. K. EARL in Molecular Autism, 8 (2017)
[article]
Titre : Clinical phenotype of ASD-associated DYRK1A haploinsufficiency Type de document : Texte imprimé et/ou numérique Auteurs : R. K. EARL, Auteur ; Tychele N. TURNER, Auteur ; H. C. MEFFORD, Auteur ; C. M. HUDAC, Auteur ; J. GERDTS, Auteur ; E. E. EICHLER, Auteur ; Raphael BERNIER, Auteur Article en page(s) : 54p. Langues : Anglais (eng) Mots-clés : Autism Clinical phenotype Dyrk1a Disruptive mutation Genetic syndrome Genetically defined subtype Index. décimale : PER Périodiques Résumé : BACKGROUND: DYRK1A is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms. METHODS: Phenotypic information from previously published DYRK1A cases (n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection (n = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender (n = 10) and to cases with an ASD-associated disruptive mutation to CHD8 (n = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents. RESULTS: DYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype. CONCLUSIONS: Results confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background. En ligne : http://dx.doi.org/10.1186/s13229-017-0173-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330
in Molecular Autism > 8 (2017) . - 54p.[article] Clinical phenotype of ASD-associated DYRK1A haploinsufficiency [Texte imprimé et/ou numérique] / R. K. EARL, Auteur ; Tychele N. TURNER, Auteur ; H. C. MEFFORD, Auteur ; C. M. HUDAC, Auteur ; J. GERDTS, Auteur ; E. E. EICHLER, Auteur ; Raphael BERNIER, Auteur . - 54p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 54p.
Mots-clés : Autism Clinical phenotype Dyrk1a Disruptive mutation Genetic syndrome Genetically defined subtype Index. décimale : PER Périodiques Résumé : BACKGROUND: DYRK1A is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms. METHODS: Phenotypic information from previously published DYRK1A cases (n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection (n = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender (n = 10) and to cases with an ASD-associated disruptive mutation to CHD8 (n = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents. RESULTS: DYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype. CONCLUSIONS: Results confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background. En ligne : http://dx.doi.org/10.1186/s13229-017-0173-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism / O. H. KIM in Molecular Autism, 8 (2017)
[article]
Titre : Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism Type de document : Texte imprimé et/ou numérique Auteurs : O. H. KIM, Auteur ; H. J. CHO, Auteur ; E. HAN, Auteur ; T. I. HONG, Auteur ; K. ARIYASIRI, Auteur ; J. H. CHOI, Auteur ; K. S. HWANG, Auteur ; Y. M. JEONG, Auteur ; S. Y. YANG, Auteur ; K. YU, Auteur ; D. S. PARK, Auteur ; H. W. OH, Auteur ; E. E. DAVIS, Auteur ; C. E. SCHWARTZ, Auteur ; J. S. LEE, Auteur ; H. G. KIM, Auteur ; C. H. KIM, Auteur Article en page(s) : 50p. Langues : Anglais (eng) Mots-clés : Autism Dyrk1a Down syndrome Group behavior Knockout Shoaling Social interaction Zebrafish Index. décimale : PER Périodiques Résumé : BACKGROUND: DYRK1A maps to the Down syndrome critical region at 21q22. Mutations in this kinase-encoding gene have been reported to cause microcephaly associated with either intellectual disability or autism in humans. Intellectual disability accompanied by microcephaly was recapitulated in a murine model by overexpressing Dyrk1a which mimicked Down syndrome phenotypes. However, given embryonic lethality in homozygous knockout (KO) mice, no murine model studies could present sufficient evidence to link Dyrk1a dysfunction with autism. To understand the molecular mechanisms underlying microcephaly and autism spectrum disorders (ASD), we established an in vivo dyrk1aa KO model using zebrafish. METHODS: We identified a patient with a mutation in the DYRK1A gene using microarray analysis. Circumventing the barrier of murine model studies, we generated a dyrk1aa KO zebrafish using transcription activator-like effector nuclease (TALEN)-mediated genome editing. For social behavioral tests, we have established a social interaction test, shoaling assay, and group behavior assay. For molecular analysis, we examined the neuronal activity in specific brain regions of dyrk1aa KO zebrafish through in situ hybridization with various probes including c-fos and crh which are the molecular markers for stress response. RESULTS: Microarray detected an intragenic microdeletion of DYRK1A in an individual with microcephaly and autism. From behavioral tests of social interaction and group behavior, dyrk1aa KO zebrafish exhibited social impairments that reproduce human phenotypes of autism in a vertebrate animal model. Social impairment in dyrk1aa KO zebrafish was further confirmed by molecular analysis of c-fos and crh expression. Transcriptional expression of c-fos and crh was lower than that of wild type fish in specific hypothalamic regions, suggesting that KO fish brains are less activated by social context. CONCLUSIONS: In this study, we established a zebrafish model to validate a candidate gene for autism in a vertebrate animal. These results illustrate the functional deficiency of DYRK1A as an underlying disease mechanism for autism. We also propose simple social behavioral assays as a tool for the broader study of autism candidate genes. En ligne : http://dx.doi.org/10.1186/s13229-017-0168-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330
in Molecular Autism > 8 (2017) . - 50p.[article] Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism [Texte imprimé et/ou numérique] / O. H. KIM, Auteur ; H. J. CHO, Auteur ; E. HAN, Auteur ; T. I. HONG, Auteur ; K. ARIYASIRI, Auteur ; J. H. CHOI, Auteur ; K. S. HWANG, Auteur ; Y. M. JEONG, Auteur ; S. Y. YANG, Auteur ; K. YU, Auteur ; D. S. PARK, Auteur ; H. W. OH, Auteur ; E. E. DAVIS, Auteur ; C. E. SCHWARTZ, Auteur ; J. S. LEE, Auteur ; H. G. KIM, Auteur ; C. H. KIM, Auteur . - 50p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 50p.
Mots-clés : Autism Dyrk1a Down syndrome Group behavior Knockout Shoaling Social interaction Zebrafish Index. décimale : PER Périodiques Résumé : BACKGROUND: DYRK1A maps to the Down syndrome critical region at 21q22. Mutations in this kinase-encoding gene have been reported to cause microcephaly associated with either intellectual disability or autism in humans. Intellectual disability accompanied by microcephaly was recapitulated in a murine model by overexpressing Dyrk1a which mimicked Down syndrome phenotypes. However, given embryonic lethality in homozygous knockout (KO) mice, no murine model studies could present sufficient evidence to link Dyrk1a dysfunction with autism. To understand the molecular mechanisms underlying microcephaly and autism spectrum disorders (ASD), we established an in vivo dyrk1aa KO model using zebrafish. METHODS: We identified a patient with a mutation in the DYRK1A gene using microarray analysis. Circumventing the barrier of murine model studies, we generated a dyrk1aa KO zebrafish using transcription activator-like effector nuclease (TALEN)-mediated genome editing. For social behavioral tests, we have established a social interaction test, shoaling assay, and group behavior assay. For molecular analysis, we examined the neuronal activity in specific brain regions of dyrk1aa KO zebrafish through in situ hybridization with various probes including c-fos and crh which are the molecular markers for stress response. RESULTS: Microarray detected an intragenic microdeletion of DYRK1A in an individual with microcephaly and autism. From behavioral tests of social interaction and group behavior, dyrk1aa KO zebrafish exhibited social impairments that reproduce human phenotypes of autism in a vertebrate animal model. Social impairment in dyrk1aa KO zebrafish was further confirmed by molecular analysis of c-fos and crh expression. Transcriptional expression of c-fos and crh was lower than that of wild type fish in specific hypothalamic regions, suggesting that KO fish brains are less activated by social context. CONCLUSIONS: In this study, we established a zebrafish model to validate a candidate gene for autism in a vertebrate animal. These results illustrate the functional deficiency of DYRK1A as an underlying disease mechanism for autism. We also propose simple social behavioral assays as a tool for the broader study of autism candidate genes. En ligne : http://dx.doi.org/10.1186/s13229-017-0168-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330