Schizophrenia Patient Shows a Rare Interleukin 15 Receptor alpha Variant Disrupting Signal Transduction

Abstract

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-15Rα) are classical immune molecules. They also help maintain normal brain function, leading to our hypothesis that IL-15Rα gene(IL- 15RA) variants contribute to the pathogenesis of schizophrenia. Objective: We determine whether the genetic variants of IL-15RA are associated with the development and progression of schizophrenia and whether IL-15RA single nucleotide polymorphism(SNP) plays a key role in downstream signaling transduction. Methods and results: We sequenced IL-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- 15Rα intracellular signal transduction. Given the similarity of symptoms of catatonic schizophrenia and the known phenotype of IL-15Rα knockout mice, gene variation might offer diagnostic value for sub-types of schizophrenia.

Reduced Serum Levels of Soluble Interleukin-15 Receptor α in Schizophrenia and Its Relationship to the Excited Phenotype

“…Notably, we also found a distinct decrease of IL-15Rα in schizophrenia patients compared to depressive patients. These observations correlated with our previous study that showed variants of the IL-15RA gene are associated with schizophrenia using IL-15RA exon sequencing ( 27 ).…”

“…Notably, we also found a distinct decrease of IL-15Rα in schizophrenia patients compared to depressive patients. These observations correlated with our previous study that showed variants of the IL-15RA gene are associated with schizophrenia using IL-15RA exon sequencing (27). Several reasons might be related to the different expression of IL-15Rα in serum between schizophrenia patients and depressive patients.…”

“…Our recently published work with RNA-seq of the cortex and hippocampus of IL-15Rα KO mice identified three functional clusters, including respiratory chain and electron transport, regulation of steroid processes, and skeletal muscle development (72). These results highlight the important role of IL-15Rα in lipid and energy metabolism, which might be mediated through STAT3 phosphorylation (27,62).…”

“…Collectively, these results indicate that IL-15Rα plays an important role in schizophrenia and depression. Furthermore, we found a rare mutation in the IL-15RA gene that impeded IL-15Rα intracellular signal transduction in schizophrenia patients ( 27 ). As the ligand of IL-15Rα, IL-15 is a cytokine especially poised to have a pivotal role in CNS organization, and it also has been reported to be a biomarker of schizophrenia and depression ( 28 – 30 ).…”

Phenotypic Resemblance to Neuropsychiatric Disorder and Altered mRNA Profiles in Cortex and Hippocampus Underlying IL15Rα Knockout

“…IL-15Rα KO mice show hyperactivity, depressive-like behavior, reduced anxiety, and impaired memory (He et al, 2010a;Pan et al, 2013). Recent studies reported a rare loss-of-function IL-15Rα mutation in a schizophrenic patient and his siblings by sequencing-the clinical manifestations were similar to IL-15Rα KO mice (Pan et al, 2019). KO mice have further abnormalities such as a leaner body composition with lower fat (He et al, 2010b), altered skeletal motor activation, elevation of body temperature, and increased energy expenditure (He et al, 2010b).…”