MicroRNAs as the cause of schizophrenia in 22q11.2 deletion carriers, and possible implications for idiopathic disease: a mini-review

Abstract

The 22q11.2 deletion is the strongest known genetic risk factor for schizophrenia. Research has implicated microRNA-mediated dysregulation in 22q11.2 deletion syndrome (22q11.2DS) schizophrenia-risk. Primary candidate genes are DGCR8 (DiGeorge syndrome critical region gene 8), which encodes a component of the microprocessor complex essential for microRNA biogenesis, and MIR185, which encodes microRNA 185. Mouse models of 22q11.2DS have demonstrated alterations in brain microRNA biogenesis, and that DGCR8 haploinsufficiency may contribute to these alterations, e.g., via down-regulation of a specific microRNA subset. miR-185 was the top-scoring down-regulated microRNA in both the prefrontal cortex and the hippocampus, brain areas which are the key foci of schizophrenia research. This reduction in miR-185 expression contributed to dendritic and spine development deficits in hippocampal neurons. In addition, miR-185 has two validated targets (RhoA, Cdc42), both of which have been associated with altered expression levels in schizophrenia. These combined data support the involvement of miR-185 and its down-stream pathways in schizophrenia. This review summarizes evidence implicating microRNA-mediated dysregulation in schizophrenia in both 22q11.2DS-related and idiopathic cases.

Copy Number Variable MicroRNAs in Schizophrenia and Their Neurodevelopmental Gene Targets

“…Such disruption is predicted to affect the functioning of the miRNAs with respect to their target genes (12). Several of the top 20 miRNA target gene sets (Figure 2) show an overlap with the most relevant functional gene-set clusters identified previously for this cohort using the protein-coding genetic content of rare deletions (3).…”

“…The study was approved by local research ethics boards, and written informed consent was obtained for each participant. Case subjects with 22q11.2 deletions were a priori excluded to prevent findings from being driven by these established risk variants (3,(10)(11)(12). The comparison sample comprised unrelated adults of European ancestry who are members of the Ontario Population Genomics Platform (OPGP) genetic epidemiological project (Supplemental Methods in Supplement 1) (3,20) and independent of the 2357 controls used for adjudication of CNV rarity (see below).…”

Five children with deletions of 1p34.3 encompassing AGO1 and AGO3

“…[5][6][7][8] In humans, the neuropsychiatric features seen in patients with 22q11.2 microdeletion syndrome are thought to result from haploinsufficiency of the DGCR8 gene and associated perturbations in miRNA biogenesis. 9 We present five patients with different but overlapping deletions involving the 1p34.3 locus, ranging in size from 1.1 to 3.1 Mb. The shared deleted region is approximately 289 kb and encompasses the AGO1 and AGO3 genes.…”

Epigenetic changes in the developing brain: Effects on behavior

“…A primary candidate gene is Dgcr8, which encodes a component of the RNA microprocessor complex (Drosha/ Dgcr8), essential for microRNA biogenesis. Mir185 in particular is the most notable down-regulated miRNA in both the prefrontal cortex and hippocampus, brain areas that are focal to schizophrenia research (89). Haploinsufficiency of Dgcr8 in a mouse model revealed synaptic SERCA2 [sarco (endo) plasmic reticulum Ca 2+ ATP-ase] overexpression, a finding that parallels the elevated levels of Ca 2+ ATP-ase found in schizophrenia brains (90).…”