A Rare Variant Which Interfered with Interleukin 15 Receptor alpha Signal Transduction Exists in Schizophrenia Patients.

Background: Schizophrenia is a complex and debilitating mental disorder with strong heritability. Its pathogenesis involves immune dysregulation. Interleukin 15 and interleukin 15 receptor alpha(IL-15R alpha) are classical immune molecules. They also help maintain normal brain function, leading to our hypothesis that IL-15R alpha gene(IL-15RA) variants contribute to the pathogenesis of schizophrenia. Objective: We determine whether the genetic variants of 1L-15RA are associated with the development and progression of schizophrenia and whether 1L-15RA single nucleotide polymorphism(SNP) plays a key role in downstream signaling transduction. Methods and Results: We sequenced 1L-15RA exon from 132 Chinese schizophrenic patients and identified a rare variant(rs528238821) in a patient diagnosed with catatonic schizophrenia and ankylosing spondylitis(AS). We overexpressed this missense variant in cells driven by pBI-CMV vector. The cells showed attenuated STAT3 phosphorylation in response to interleukin15. Conclusion: IL-15RA mutation is rare in schizophrenic patients but interfered with IL-15R alpha intracellular signal transduction. Given the similarity of symptoms of catatonic schizophrenia and the known phenotype of IL-15R alpha knockout mice, gene variation might offer diagnostic value for sub-types of schizophrenia.