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

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Abstract
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.
Funding Information
  • HHS | NIH | National Institute of Mental Health (MH097879)
  • HHS | NIH | National Institute of Mental Health (MH097879)
  • HHS | NIH | National Institute of Mental Health (MH097879)
  • HHS | NIH | National Institute of Mental Health (MH097879)
  • HHS | NIH | National Institute of Mental Health (MH097879)
  • HHS | NIH | National Institute of Mental Health (MH097879)
  • HHS | NIH | National Institute of Mental Health (MH097879)

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