CACNA1G, A Heterotaxy Candidate Gene, Plays a Role in Ciliogenesis and Left-Right Patterning in Xenopus tropicalis

Abstract

Heterotaxy (HTX) is characterized by an abnormality in the organ arrangement along the Left-Right (LR) axis and is caused by the disruption of LR patterning in early development. LR asymmetry is critical for multiple organs. Specifically, proper LR patterning is crucial for cardiac function and is a cause of congenital heart disease (CHD). CACNA1G is a candidate gene identified in patients with CHD and HTX. This gene encodes a T-type, low-voltage-activated calcium channel and is a member of the Cav3.1 channel family. However, its function in cardiac or embryonic development remains unknown. Here, we show that abnormal cacna1g expression in Xenopus tropicalis recapitulates the HTX phenotype found in the patient cohort. By examining early LR patterning markers, including pitx2c and dand5, we discovered that both markers are expressed abnormally, suggesting that LR patterning is disrupted at the earliest stages of the LR signaling cascade. Since cilia have been described as key regulators of LR asymmetry, we checked the process of cilia formation in cacna1g crispants. The LR Organizer (LRO) contained reduced cilia quantity in the cacna1g crispants, which may explain the LR defects. In conclusion, the abnormal expression of cacna1g affects cilia in the LRO, leading to abnormal LR patterning and cardiac looping.