The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

Abstract

It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.

The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

“…Recent technological advances have enabled the reproduction of pathological conditions in vitro by creating patient-derived or mutation-carrying induced pluripotent stem (iPS) cells and then differentiating them into central nervous system cells or miniature brains. Studies of etiologically valid cellular models of schizophrenia produced with this technology, including those with 22q11.2 deletion, 16p11.2 deletion/duplication, SETD1A LOF/PTV, and NRXN LOF/PTV, have been conducted and reported [94][95][96][97][98][99][100][101][102][103][104][105][106] (Table 3).…”

“…Also, morphological alteration of soma and dendrite were common except for iPS cell-derived neurons with NRXN1 deletion [94,98,101,102,106]. Abnormal neural activities are identified in multiple patient-derived or genetically engineered iPS cellderived neurons, however, the directions of the abnormalities are sometimes inconsistent across models manipulating different genes [97,[101][102][103][104][105][106]. Though it may be due to artifacts depending on the differences in the experimental designs, another possibility is that imbalanced excitatory/inhibitory activities themselves [107], regardless of the direction of abnormality, are important in schizophrenia pathology.…”

Astrocytic cell adhesion genes linked to schizophrenia correlate with synaptic programs in neurons

“…To study molecular pathways in glia-neuron interactions, we first assembled a sample set of 32 karyotypically normal hPSC lines (29 iPSC and three ESC lines) derived from neurotypical donors 15,18 Figure 1, Table S1 ). These lines were differentiated into excitatory neurons using a well-characterized protocol that combines Ngn2 expression with forebrain patterning factors to robustly generate a homogenous population of excitatory neurons (N= 32 cell lines) 15 .…”

Different Types of Deletions Created by Low-Copy Repeats Sequences Location in 22q11.2 Deletion Syndrome: Genotype–Phenotype Correlation

“…Although 22q11.2DS is a contiguous gene syndrome, the size of the deletion does not influence the severity of the phenotypic manifestations: LCR A–D deletions most often present similar phenotype and severity compared to smaller proximal deletion (LCR A–B) [ 53 , 54 ]. However, it was observed that central (LCR B–D) and distal deletions (LCR D–E/F) usually have a milder phenotype [ 55 ], a fact also observed in our study; at the same time, the incomplete penetrance and variable expressivity can also be noticed, especially in inherited deletions, where the same size and type of deletion can determine a severe phenotype but also a discrete or even asymptomatic one.…”