ST8SIA2 – Schizophrenia

ST8SIA2 encodes a polysialyltransferase responsible for the addition of polysialic acid (PSA) chains to the neural cell adhesion molecule NCAM1, a modification critical for neurodevelopment and synaptic plasticity. Linkage at 15q26 prompted candidate gene studies across diagnostic boundaries, focusing on schizophrenia and bipolar I disorder.

Case–control association studies in a Korean cohort (582 schizophrenia patients, 502 controls) identified 14 of 34 tag SNPs with nominal significance and the strongest signal at rs11637898 under a dominant model (p = 0.0033; combined schizophrenia and BD-I p = 0.0006) ([PMID:26418860]). A Han Chinese study (643 schizophrenics, 527 controls) found rs3759915 associated with schizophrenia (p = 0.0036) and promoter haplotypes (rs3759915–rs3759914–rs3759916) showing a global P = 0.0000050 under linkage disequilibrium ([PMID:17126533]). No linkage was observed for bipolar II disorder.

Targeted resequencing in bipolar disorder cases uncovered one synonymous coding variant, c.621C>T (p.Pro207=), and multiple noncoding UTR and intronic SNPs potentially affecting ST8SIA2 expression, but no loss-of-function alleles were detected ([PMID:24651862]). Promoter polymorphisms in SIAT8B (ST8SIA2) such as –1126T>C and –851T>C increased reporter activity in vitro (p = 0.021), supporting functional impact of risk haplotypes ([PMID:16229822]).

In vivo, St8sia2⁻/⁻ mice exhibit schizophrenia-like endophenotypes, including enlarged lateral ventricles, reduced thalamic volume, disorganized thalamocortical fibers, impaired working memory and prepulse inhibition, anhedonia, and amphetamine hypersensitivity, recapitulating human disease features ([PMID:24057454]). These findings implicate haploinsufficiency of ST8SIA2 and consequent disruption of PSA-NCAM1 in the pathogenesis of schizophrenia.

Integration & Conclusion: Although common SNP associations across multiple populations and concordant functional data in knockout models support a biological role for ST8SIA2 in schizophrenia susceptibility, the absence of rare Mendelian variants and familial segregation yields limited clinical validity under ClinGen criteria. Further large-scale sequencing and segregation studies are needed.

Key Take-home: ST8SIA2 variation modulates schizophrenia risk through dysregulated polysialylation of NCAM1, offering a potential biomarker and therapeutic target pending validation in deep-sequencing and family-based studies.

References

• PLoS one • 2015 • Association between ST8SIA2 and the Risk of Schizophrenia and Bipolar I Disorder across Diagnostic Boundaries. PMID:26418860
• Schizophrenia research • 2007 • Positive association between SIAT8B and schizophrenia in the Chinese Han population. PMID:17126533
• PLoS one • 2014 • Characterisation of genetic variation in ST8SIA2 and its interaction region in NCAM1 in patients with bipolar disorder. PMID:24651862
• Biological psychiatry • 2006 • Association between polymorphisms in the promoter region of the sialyltransferase 8B (SIAT8B) gene and schizophrenia. PMID:16229822
• Brain structure & function • 2015 • Schizophrenia-like phenotype of polysialyltransferase ST8SIA2-deficient mice. PMID:24057454

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