Fig. 1: SETD1A haploinsufficiency causes neurodevelopmental abnormalities. | Nature Communications

Fig. 1: SETD1A haploinsufficiency causes neurodevelopmental abnormalities.

From: SETD1A regulates psychiatric gene networks involved in genomic stability and synaptic function in rare and sporadic schizophrenia

Fig. 1: SETD1A haploinsufficiency causes neurodevelopmental abnormalities.The alternative text for this image may have been generated using AI.

a Schematic of targeted pathogenic SETD1A loss-of-function variant (c.4582-2delAG). Intron 15 retention causes frame-shifted exon 16 with premature stop codon. b Isogenic iPSC lines from two individuals. Six SETD1A+/− and three WT from LIBD2c1; two SETD1Ac.4582-2delAG/+, four SETD1A+/−, three WT from LIBD7c6. All SETD1A+/− carry premature stop codons. c Chromatograms showing WT and mutant alleles with c.4582-2delAG mutation. d Representative images of iPSCs, NPCs, neurons, cerebral organoids from WT and SETD1Ac.4582-2delAG/+. Nuclei: Hoechst. Scale: 50 μm (iPSC, organoids); 20 μm (NPC); 10 μm (neurons). e SETD1A expression in iPSCs (n = 2 technical replicates), NPCs (n = 3 technical replicates), 4-week neurons (n = 1 or 4 technical replicates), day-48 cerebral organoids (n = 2 technical replicates) from six WT, six SETD1A+/− including two SETD1Ac.4582-2delAG/+, normalized to GAPDH. Mann–Whitney test, **p = 0.0051; ***p = 0.0005; ****p < 0.0001. Unpaired t-test, *p = 0.015. f SETD1A transcript frequencies between exons 15–16 in NPCs and 4–6-week neurons from six WT, six SETD1A+/−. Binomial test, ****p < 0.0001. g Western blots showing reduced full-length SETD1A and absent truncated protein in SETD1Ac.4582-2delAG/+ NPCs/neurons. h Histone H3K4 methylation in NPCs from two WT (n = 2 technical replicates), two SETD1Ac.4582-2delAG/+ (n = 3 technical replicates), normalized to H3. Unpaired t-test, *p = 0.0208. i NPC proliferation over 3 days from six WT (n = 3 or 7 technical replicates), six SETD1A+/− (n = 3, 6, or 7 technical replicates). Unpaired t-test, ***p = 0.0003. j Schematic of experimental procedures. k SYN-RFP-labeled 6-week neurons. Scale: 100 μm. l Sholl analysis from three WT (n = 56 cells), two SETD1Ac.4582-2delAG/+ (n = 40 cells). Two-way ANOVA with Bonferroni’s test, ***p = 0.0003 (60 µm); ***p = 0.0002 (70 µm); **p = 0.0019 (160 µm); *p = 0.0191 (170 µm); ****p < 0.0001 (50, 80–150 µm). m Raster plots showing neuronal bursts (60 s) at weeks 8, 11. Blue = network bursts. n MEA recordings (6–13 weeks): firing rates, synchrony index, inter-network burst intervals from WT (six lines), SETD1A+/− (six lines) including two SETD1Ac.4582-2delAG/+. Scheirer-Ray-Hare test with Dunn’s tests, **p = 0.0038 (week 8); **p = 0.0024 (week 9) for mean firing rate; **p = 0.0275 (week 9) for synchrony index; *p = 0.0223 (week 7); **p = 0.0086 (week 8); *p = 0.0102 (week 9) for inter-network burst-interval. All tests two-sided except (f) (one-sided). Mean ± S.D. (e, h, i); Mean ± S.E.M. (l); Median with interquartile range (n). Source data provided as Source Data file.

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