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Publication : Loss-of-function mutation in <i>Mirta22/Emc10</i> rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion.

First Author  Diamantopoulou A Year  2017
Journal  Proc Natl Acad Sci U S A Volume  114
Issue  30 Pages  E6127-E6136
PubMed ID  28696314 Mgi Jnum  J:243862
Mgi Id  MGI:5912641 Doi  10.1073/pnas.1615719114
Citation  Diamantopoulou A, et al. (2017) Loss-of-function mutation in Mirta22/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion. Proc Natl Acad Sci U S A 114(30):E6127-E6136
abstractText  Identification of protective loss-of-function (LoF) mutations holds great promise for devising novel therapeutic interventions, although it faces challenges due to the scarcity of protective LoF alleles in the human genome. Exploiting the detailed mechanistic characterization of animal models of validated disease mutations offers an alternative. Here, we provide insights into protective-variant biology based on our characterization of a model of the 22q11.2 deletion, a strong genetic risk factor for schizophrenia (SCZ). Postnatal brain up-regulation of Mirta22/Emc10, an inhibitor of neuronal maturation, represents the major transcriptional effect of the 22q11.2-associated microRNA dysregulation. Here, we demonstrate that mice in which the Df(16)A deficiency is combined with a LoF Mirta22 allele show rescue of key SCZ-related deficits, namely prepulse inhibition decrease, working memory impairment, and social memory deficits, as well as synaptic and structural plasticity abnormalities in the prefrontal cortex. Additional analysis of homozygous Mirta22 knockout mice, in which no alteration is observed in the above-mentioned SCZ-related phenotypes, highlights the deleterious effects of Mirta22 up-regulation. Our results support a causal link between dysregulation of a miRNA target and SCZ-related deficits and provide key insights into beneficial LoF mutations and potential new treatments.
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