Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling / Nicole C. SHAW in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 42p. Titre : Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling Type de document : Texte imprimé et/ou numérique Auteurs : Nicole C. SHAW, Auteur ; Kevin CHEN, Auteur ; Kathryn O. FARLEY, Auteur ; Mitchell HEDGES, Auteur ; Catherine FORBES, Auteur ; Gareth BAYNAM, Auteur ; Timo LASSMANN, Auteur ; Vanessa S. FEAR, Auteur Article en page(s) : 42p. Langues : Anglais (eng) Mots-clés : Induced Pluripotent Stem Cells/metabolism/cytology  Humans  Haploinsufficiency  Cell Differentiation  Carrier Proteins/genetics  Nuclear Proteins/genetics/metabolism  Mutation  GATA2 Transcription Factor/genetics/metabolism  Neurons/metabolism  Neural Stem Cells/metabolism  Wnt Signaling Pathway/genetics  Intellectual Disability/genetics  Phenotype  Crispr  Neural cell modelling  Neurodevelopmental disorders  SETBP1 haploinsufficiency disorder  Variants of unknown significance  iPSC Index. décimale : PER Périodiques Résumé : BACKGROUND: SETBP1 Haploinsufficiency Disorder (SETBP1-HD) is characterised by mild to moderate intellectual disability, speech and language impairment, mild motor developmental delay, behavioural issues, hypotonia, mild facial dysmorphisms, and vision impairment. Despite a clear link between SETBP1 mutations and neurodevelopmental disorders the precise role of SETBP1 in neural development remains elusive. We investigate the functional effects of three SETBP1 genetic variants including two pathogenic mutations p.Glu545Ter and SETBP1 p.Tyr1066Ter, resulting in removal of SKI and/or SET domains, and a point mutation p.Thr1387Met in the SET domain. METHODS: Genetic variants were introduced into induced pluripotent stem cells (iPSCs) and subsequently differentiated into neurons to model the disease. We measured changes in cellular differentiation, SETBP1 protein localisation, and gene expression changes. RESULTS: The data indicated a change in the WNT pathway, RNA polymerase II pathway and identified GATA2 as a central transcription factor in disease perturbation. In addition, the genetic variants altered the expression of gene sets related to neural forebrain development matching characteristics typical of the SETBP1-HD phenotype. LIMITATIONS: The study investigates changes in cellular function in differentiation of iPSC to neural progenitor cells as a human model of SETBP1 HD disorder. Future studies may provide additional information relevant to disease on further neural cell specification, to derive mature neurons, neural forebrain cells, or brain organoids. CONCLUSIONS: We developed a human SETBP1-HD model and identified perturbations to the WNT and POL2RA pathway, genes regulated by GATA2. Strikingly neural cells for both the SETBP1 truncation mutations and the single nucleotide variant displayed a SETBP1-HD-like phenotype. En ligne : https://dx.doi.org/10.1186/s13229-024-00625-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling [Texte imprimé et/ou numérique] / Nicole C. SHAW, Auteur ; Kevin CHEN, Auteur ; Kathryn O. FARLEY, Auteur ; Mitchell HEDGES, Auteur ; Catherine FORBES, Auteur ; Gareth BAYNAM, Auteur ; Timo LASSMANN, Auteur ; Vanessa S. FEAR, Auteur . - 42p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 42p. Mots-clés : Induced Pluripotent Stem Cells/metabolism/cytology  Humans  Haploinsufficiency  Cell Differentiation  Carrier Proteins/genetics  Nuclear Proteins/genetics/metabolism  Mutation  GATA2 Transcription Factor/genetics/metabolism  Neurons/metabolism  Neural Stem Cells/metabolism  Wnt Signaling Pathway/genetics  Intellectual Disability/genetics  Phenotype  Crispr  Neural cell modelling  Neurodevelopmental disorders  SETBP1 haploinsufficiency disorder  Variants of unknown significance  iPSC Index. décimale : PER Périodiques Résumé : BACKGROUND: SETBP1 Haploinsufficiency Disorder (SETBP1-HD) is characterised by mild to moderate intellectual disability, speech and language impairment, mild motor developmental delay, behavioural issues, hypotonia, mild facial dysmorphisms, and vision impairment. Despite a clear link between SETBP1 mutations and neurodevelopmental disorders the precise role of SETBP1 in neural development remains elusive. We investigate the functional effects of three SETBP1 genetic variants including two pathogenic mutations p.Glu545Ter and SETBP1 p.Tyr1066Ter, resulting in removal of SKI and/or SET domains, and a point mutation p.Thr1387Met in the SET domain. METHODS: Genetic variants were introduced into induced pluripotent stem cells (iPSCs) and subsequently differentiated into neurons to model the disease. We measured changes in cellular differentiation, SETBP1 protein localisation, and gene expression changes. RESULTS: The data indicated a change in the WNT pathway, RNA polymerase II pathway and identified GATA2 as a central transcription factor in disease perturbation. In addition, the genetic variants altered the expression of gene sets related to neural forebrain development matching characteristics typical of the SETBP1-HD phenotype. LIMITATIONS: The study investigates changes in cellular function in differentiation of iPSC to neural progenitor cells as a human model of SETBP1 HD disorder. Future studies may provide additional information relevant to disease on further neural cell specification, to derive mature neurons, neural forebrain cells, or brain organoids. CONCLUSIONS: We developed a human SETBP1-HD model and identified perturbations to the WNT and POL2RA pathway, genes regulated by GATA2. Strikingly neural cells for both the SETBP1 truncation mutations and the single nucleotide variant displayed a SETBP1-HD-like phenotype. En ligne : https://dx.doi.org/10.1186/s13229-024-00625-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

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