Mutations of schizophrenia risk gene SETD1A dysregulate synaptic function in human neurons

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Schizophrenia (SCZ) is a complex disorder influenced by common and rare genetic variants.
• Rare premature termination variants in SETD1A are strongly associated with SCZ risk.
• The precise mechanisms by which SETD1A variants contribute to SCZ pathophysiology remain largely unknown.

Purpose of the Study:

• To investigate the impact of rare premature open reading frame (ORF) termination variants in SETD1A on human neurons.
• To elucidate the cellular and molecular consequences of SETD1A haploinsufficiency in the context of SCZ.

Main Methods:

• CRISPR/Cas9 gene editing was used to engineer human induced pluripotent stem cells (iPSCs) with patient-specific SETD1A mutations (c.4582-2delAG and c.4596_4597insG).
• Nonsense-mediated decay (NMD) of SETD1A mRNA and subsequent reduction in full-length SETD1A protein levels were analyzed.
• iPSC-derived excitatory neurons (induced by NGN2) with SETD1A haploinsufficiency (SETD1A+/-) were characterized for morphological, electrophysiological, and transcriptomic changes.

Main Results:

• Engineered SETD1A mutations led to nonsense-mediated decay (NMD) and reduced SETD1A protein levels, confirming loss-of-function (LoF) phenotypes.
• SETD1A haploinsufficiency in iPSC-derived neurons altered dendritic complexity.
• SETD1A+/- mutations dysregulated synaptic transmission and plasticity, associated with altered expression of synaptic function genes.

Conclusions:

• SETD1A haploinsufficiency due to premature termination variants results in significant neuronal alterations.
• These findings provide mechanistic insights into how SETD1A loss-of-function mutations contribute to neuron phenotypes relevant to schizophrenia pathophysiology.
• The study highlights the role of SETD1A in maintaining normal neuronal function and synaptic integrity.