DOC2A – Schizophrenia

The association between DOC2A and schizophrenia is supported by both genetic and functional evidence. A large-scale copy number variation (CNV) analysis in schizophrenia cases identified recurrent duplications in DOC2A, with 10 affected individuals showing a duplication of this key calcium-signaling gene (PMID:20489179). These findings were observed in two independent cohorts, underscoring the reproducibility of the genetic signal despite limited family segregation data.

In terms of genetic evidence, the CNV study evaluated nearly a thousand cases in the primary cohort and confirmed the observation in an independent cohort. Although the segregation data remains sparse, the recurrence of DOC2A duplications in multiple unrelated individuals provides robust support for its involvement in schizophrenia pathogenesis (PMID:20489179). The genetic findings suggest that CNVs affecting DOC2A may alter gene dosage and contribute to synaptic dysfunction.

Complementary functional studies have further delineated the role of DOC2A in neuronal activity. Experimental assessments demonstrated that DOC2A acts as a calcium sensor with unique calcium-dependent translocation properties, thereby influencing synaptic vesicle docking and neurotransmitter release (PMID:16515538). Additional work has shown that alterations in DOC2A stability and proper synaptic targeting, particularly in the context of interacting proteins such as Munc18-1, may exacerbate synaptic dysregulation (PMID:38242640).

Integrating the genetic and functional data, the evidence indicates that disruptions in DOC2A contribute to altered synaptic transmission processes that are central to the neurobiology of schizophrenia. Although comprehensive segregation analyses are not available, the repeated identification of DOC2A CNVs and the supportive experimental findings provide a biologically plausible mechanism that links gene dosage changes to clinical phenotypes observed in schizophrenia.

The cumulative evidence thus falls within the ClinGen guidelines for a strong gene–disease association. Future investigations aiming to detail the inheritance pattern of DOC2A alterations and their effect on synaptic function will further enhance the clinical utility of these findings in diagnostic decision‑making and risk stratification for schizophrenia.

Key Take‑home: Alterations in DOC2A significantly impact synaptic physiology, supporting its clinical relevance as a risk factor for schizophrenia.

References

• Proceedings of the National Academy of Sciences of the United States of America • 2010 • Strong synaptic transmission impact by copy number variations in schizophrenia PMID:20489179
• Journal of Neurochemistry • 2006 • DOC2A and DOC2B are sensors for neuronal activity with unique calcium‑dependent and kinetic properties PMID:16515538
• Brain: a journal of neurology • 2024 • Disease‑linked mutations in Munc18‑1 deplete synaptic Doc2 PMID:38242640

Evidence Based Scoring (AI generated)