NIH Pub Med.gov
Pflugers Arch. 2010 Jul;460(2):353-9. Epub 2009 Nov 15.
National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore. Ping_LIAO@nni.com.sg
Mutations of human CaV1.2 channel gene were identified only recently. The gain-of-function mutations were found at two mutually exclusive exons in patients with Timothy syndrome (TS). These patients exhibit prolonged QT interval and lethal cardiac arrhythmias. In contrast, the loss-of-function mutations of CaV1.2 channel in patients with Brugada syndrome produce short QT interval that could result in sudden cardiac death. TS patients also suffer from multi-organ dysfunction that includes neurological disorder such as autism and mental retardation reflecting the wide tissue distribution of CaV1.2 channel. Mutations found on different mutually exclusive exons determine the severity of the disease. Unexpectedly, TS patients may develop recurrent infections and bronchitis that suggests a role of CaV1.2 channel in the immune system. Furthermore, recent reports revealed a linkage of CaV1.2 channel polymorphism with multiple central nervous system disorders including bipolar disorder, depression, and schizophrenia. Here, we will discuss how alternative splicing modulates CaV1.2 channelopathy and the role of CaV1.2 channel in both excitable and non-excitable tissues.