About: Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome

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About: Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome
Creator	Bahr, Angela Bodamer, Olaf Casey, Alicia Cho, Megan Co, Calvin Engleman, Kendra Genetti, Casie Gilissen, Christian Higgs, Martin Hoefele, Julia Joset, Pascal Keller, Elmar Kleefstra, Tjitske Koolen, David Kramer, Jamie Kummeling, Joost Mcwalter, Kirsty Pfundt, Rolph Raas-Rothschild, Annick Rauch, Anita Raun, Nicholas Rf, Margot Riedhammer, Korbinian Ruiterkamp-Versteeg, Martina Schepens, Marga Schwaibold, Eva Simon, Marleen Sinnema, Margje Steindl, Katharina Stremmelaar, Diante Terhal, Paulien Thiffault, Isabelle Van Der Smagt, Jasper Van Gassen, Koen Wheless, James Willemsen, Marjolein Zhou, Dihong
Source	BioRxiv
abstract	Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as Loss-of-Function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila Melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.
has issue date	2019-12-18(xsd:dateTime)
bibo:doi	10.1101/2019.12.17.879189
has license	biorxiv
sha1sum (hex)	da8a74ef5d62f7e3a3ea17695dbd02c1565e9647
schema:url	https://doi.org/10.1101/2019.12.17.879189
resource representing a document's title	Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome
schema:publication	bioRxiv
resource representing a document's body	covid:da8a74ef5d62f7e3a3ea17695dbd02c1565e9647#body_text
is schema:about of	named entity 'orthologue' named entity 'comparable' named entity 'involved' named entity 'DNA damage' named entity 'demonstrated' named entity 'cellular' named entity 'proliferation' named entity 'Characterization' named entity 'ROLE' named entity 'HISTONE METHYLTRANSFERASES' named entity 'ORTHOLOGUE' named entity 'FACIAL DYSMORPHISMS' named entity 'STUDY' covid:arg/da8a74ef5d62f7e3a3ea17695dbd02c1565e9647 named entity 'symptoms' named entity 'processes' named entity 'Heterozygous' named entity 'study' named entity 'catalytic' named entity 'features' named entity 'patient' named entity 'microcephaly' named entity 'define' named entity 'cognitive functioning' named entity 'set' named entity 'schizophrenia' named entity 'neurodevelopmental disorder' named entity 'repair' named entity 'Loss-of-Function' named entity 'haploinsufficiency' named entity 'SET domain' named entity 'psychiatric problems' named entity 'schizophrenia' named entity 'DNA damage repair' named entity 'histone H3' named entity 'neurons' named entity 'methylation' named entity 'RNAi' named entity 'Mendelian' named entity 'euphoria' named entity 'protein family' named entity 'GFP' named entity 'long-term' named entity 'cell proliferation' named entity 'negative symptoms' named entity 'base pair' named entity 'SET domain' named entity 'postmitotic'

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