Retinoic acid inducible-1 gene (RAI1) and clinical subtypes of schizophrenia. In: Li-Hong C and Yuto I, eds. Retinoic acid: Structure, Metabolism and Roles in Disease.

Abstract

Schizophrenia is a common neuropsychiatric disorder affecting approximately 1% of the general population and displaying considerable heterogeneity of symptoms, course and outcomes. It is generally considered to be a neurodevelopmental disorder that ultimately affects forebrain neurons and circuits. Retinoid signaling is involved in fetal brain development, affecting patterning and neuronal differentiation, and in the maintenance and regulation of neuronal plasticity in different areas of the adult forebrain. Therefore, there may be a relationship between retinoid signaling and perturbation involved in brain development and neuronal plasticity in schizophrenia. Studies of the genes coding proteins participating in retinoid metabolism and transport, retinoid signaling pathway, as well as retinoic acid-responsive genes, are needed to elucidate this relationship. To make contribution to this understudied area, we present here our recent findings of a potential associations between the retinoic acid inducible-1 (RAI1) gene and schizophrenic patients of European descent. RAI1 is retinoic acid-responsive gene expressed at high levels in the neuronal and heart structures, and acts as transcription regulator with role in neuronal development and differentiation, and neurobehavioral regulation. It contains polymorphic CAG repeats coding for glutaminerich activation domain, involved in protein-protein interaction that can be modulated by the number of repeats. Our population-based case-control study showed that the number of CAG repeats in the RAI1 gene ranged from 8 to 19 in the group of 115 unrelated patients, with the most frequent allele with 13 repeats, and from 10 to 19 in the group of 100 controls, with the most frequent allele with 14 repeats. When alleles were divided as ≤13 and >13 repeats, alleles ≤13 repeats appeared significantly more often in patient group (57.6% patients vs. 47% controls; χ2=13813.0; p=.015). Paranoid, disorganized, undifferentiated, and residual subtypes of schizophrenia displayed similar allelic distributions (p=.208, Pearson‘s chi-square test), which might be misleading as stratification of sample reduced number of patients in each subgroup. When PANSS (Positive and Negative Syndrome Scale) scores based stratification was analyzed, significant association between alleles ≤13 repeats and positive forms of schizophrenia was obtained (χ2=7.675; p=.021). As patients with prominent delusions, hallucinations and/or disorganized speech and behavior displayed significantly shorter CAG repeat size compared to patients with predominant negative symptoms, our finding suggests that polyglutamine polymorphism in RAI1 gene may underlie processes at certain brain structures related to productive symptomatology. Polyglutamine polymorphism may affect RAI1 interaction with partner proteins, modulating its function and thus altering developmental and neuroplastic retinoid signaling in the brain.