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Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome
- Source :
- Molecular Psychiatry, 26(6), 2013-2024. Nature Publishing Group, Molecular Psychiatry, 26, 6, pp. 2013-2024, Molecular Psychiatry, 26, 2013-2024
- Publication Year :
- 2019
-
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.
- Subjects :
- 0301 basic medicine
Microcephaly
Methyltransferase
HISTONE H3K4 METHYLASES
PROTEIN
Haploinsufficiency
OF-FUNCTION VARIANTS
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Neurodevelopmental disorder
Intellectual Disability
SCHIZOPHRENIA
medicine
Animals
Humans
Global developmental delay
Allele
Child
Molecular Biology
030304 developmental biology
Genetics
0303 health sciences
Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]
biology
COMPASS FAMILY
GENETIC-VARIATION
Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6]
Histone-Lysine N-Methyltransferase
medicine.disease
biology.organism_classification
SELFISH SPERMATOGONIAL SELECTION
Psychiatry and Mental health
030104 developmental biology
Drosophila melanogaster
PATERNAL AGE
DE-NOVO MUTATIONS
Neurodevelopmental Disorders
Histone methyltransferase
Drosophila
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 14765578 and 13594184
- Volume :
- 26
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Molecular psychiatry
- Accession number :
- edsair.doi.dedup.....f241beaeed4a1d131576c448fdbcf8bc