The 22q11.2 microdeletion: fifteen years of insights into the genetic and neural complexity of psychiatric disorders

Abstract

Over the last fifteen years it has become established that 22q11.2 deletion syndrome (22q11DS) is a true genetic risk factor for schizophrenia. Carriers of deletions in chromosome 22q11.2 develop schizophrenia at rate of 25-30% and such deletions account for as many as 1-2% of cases of sporadic schizophrenia in the general population. Access to a relatively homogeneous population of individuals that suffer from schizophrenia as the result of a shared etiological factor and the potential to generate etiologically valid mouse models provides an immense opportunity to better understand the pathobiology of this disease. In this review we survey the clinical literature associated with the 22q11.2 microdeletions with a focus on neuroanatomical changes. Then, we highlight results from work modeling this structural mutation in animals. The key biological pathways disrupted by the mutation are discussed and how these changes impact the structure and function of neural circuits is described.

Figure 1. Function of protein palmitoylation in neurons affected by hemizygosity of the palmitoyl transferase ZDHHC8

Palmitoyl transferases are primarily localized to the Golgi apparatus although there is evidence that ZDHHC8 is also found in dendrites. Such enzymes modify proteins by addition of the 16-carbon palmitate lipid group at cysteine residues. This modification increases protein hydrophobicity and, hence, increases their interaction with the plasma membrane and with intracellular membranes, such a sorting vesicles. Shown is the modification of PSD-95, which has been shown to be a substrate of ZDDHC8 – decreased PSD-95 localization at synapses may be due to 1) decreased palmitoylation at the Golgi apparatus (left) or 2) reduced local palmitoylation at the synapse (right).

Figure 2. Dysregulation of miRNA biogenesis and alteration of gene expression patterns in 22q11.2 animal models

Both the Dgcr8 and mir-185 genes are located within the 1.5-Mb microdeletion region within chromosome 22q11.2 and the equivalent region of mouse chromosome 16. Hence, they are hemizygous in the microdeletion syndrome. This deficit results in a reduction in the levels of a subset of mature miRNAs (red, blue) in both PFC and HPC in Df(16)A+/− mice. mir-185 expression is particularly affected due to the combination of hemizygosity and reduced synthesis due to Dgcr8 hemizygosity, hence its down-regulation is stronger than other miRNAs (indicated by a thicker arrow). Partial reduction in miRNA levels can affect mRNA and protein levels of target genes. Moreover, since target mRNAs can be regulated by the combinational control of more than one miRNA, the level of repression achieved may be highly sensitive to the amount and types of available miRNA complexes. Therefore, miRNA dysregulation is a molecular pathway strongly affected in 22q11.2DS. For example, target genes may be upregulated due to reduction of miRNAs affected by the Dgcr8 deficiency (bottom left), due to reduction of miRNA genes removed by the 22q11.2 microdeletion (mir-185 within the 1.5-MB minimal region is shown as an example here, bottom right), or due to a combination of both (bottom middle). The alteration of target gene expression patterns could result in a number of phenotypic abnormalities controlled by these target genes.

Figure 3. Shown is a schematic of a cortical synapse in Prodh deficient mice (right) compared to a wild type synapse (left)

There is evidence of increased dopaminergic tone in the cortex of in Prodh deficient mice. Such mice show increased expression of Comt as a presumed compensatory mechanism to this change, in addition to decreased expression of D1 receptors and Darpp32 and increased expression of calcineurin. Increased dopaminergic tone is likely to underlie hypersensitivity to amphetamine challenge and potentially other behavioral changes in these mice.