CACNA1C encodes the pore-forming subunit of the CaV1.2 L-type Ca2+ channel, a crucial component in membrane physiology across multiple tissues like the heart, brain, and immune system [1]. This channel is involved in various cellular functions, and the gene's role is of great biological importance in understanding physiological and pathological processes. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, can be valuable for studying CACNA1C.

Mutations in CACNA1C can lead to a wide range of disorders. Timothy syndrome (TS), a severe multisystem disorder, is characterized by neurodevelopmental deficits, long-QT syndrome, cardiac arrhythmias, craniofacial abnormalities, and immune deficits [1]. Additionally, CACNA1C-related disorders can present with more selective phenotypes, such as predominantly cardiac or neurological symptoms. Some individuals with heterozygous variants in CACNA1C show neurological manifestations like developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy [2]. Functional studies of missense variants via patch-clamp experiments demonstrated differential effects on channel function in vitro, including loss of function, neutral effect, and gain of function [2]. Large-scale genome-wide association studies have shown that genetic variation in CACNA1C increases the risk for psychiatric disorders, and research has focused on uncovering the underlying biological mechanisms [3]. Meta-analyses suggest that CACNA1C (rs1006737) may be a susceptibility gene for schizophrenia [4]. Pharmacoepidemiological evidence indicates that calcium channel blockers targeting L-type calcium channels (LTCCs) encoded by CACNA1C might have beneficial effects on the onset or course of psychiatric disorders [5]. Also, CACNA1C-rs1006737 polymorphisms are slightly associated with cognitive performance in severe mental disorders [6]. In ovarian cancer, CACNA1C has lower expression in tumor tissues, is an independent risk factor of overall survival, and is associated with immunity [7].

In conclusion, CACNA1C is essential for membrane physiology in multiple tissues. Model-based research, such as KO or CKO mouse models (not directly described in provided references but emphasized as valuable approach), could potentially further clarify its role in various disease areas including multisystem disorders, neurological and psychiatric conditions, and ovarian cancer. Understanding CACNA1C is crucial for unravelling the mechanisms of these diseases and may offer new directions for treatment.