Characterizing rare mis-sense variations of CACNA1I identified in a Swedish schizophrenia cohort

Abstract

CACNA1I (hCa_V3.3) encodes the α1 pore-forming subunit of human voltage-gated T-type calcium channels. Ca_V3.3 is expressed in a limited subset of neurons including GABAergic neurons of the thalamic reticular nucleus (TRN) where they support oscillatory activity essential for sleep spindle generation. CACNA1I is implicated in schizophrenia risk by emerging genetics including genome-wide association studies (PGC, 2014), and exome sequencing of trio samples (Gulsuner et al., 2013). In order to understand the impact of disease-associated sequence variation on the function of Ca_V3.3, we set out to analyze a complete set of rare mis-sense coding variations in CACNA1I in a Swedish cohort, including 15 variations identified in patients, 20 identified in control subjects, and 23 in both. We established a heterologous expression system of isogenic cell lines, each carrying single-copy inducible cDNA variants of hCa_V3.3, and evaluated their functional impact on channel function by electrophysiology, calcium imaging, and biochemistry. We found at least five coding variations impaired overall channel protein abundance, as well as whole cell current density. In addition, we identified hCa_V3.3 variants with altered voltage-dependence of channel activation and inactivation. Overall, we found that reduced calcium influx through hCa_V3.3 is associated with the group of variants identified in patients, compared to those in both patients and controls. Our findings suggest that patient-specific rare variations of CACNA1I may influence channel-dependent functions, including rebound bursting in TRN neurons, with potential implications for schizophrenia pathophysiology.

Disclosure of interest

The authors have not supplied their declaration of competing interest.