Jph3, encoding junctophilin 3, is a gene whose protein product serves to stabilize junctional membrane complexes between the plasma membrane and endoplasmic reticulum and regulate neuronal calcium flux [4,5]. Junctophilins play essential roles in developing and maintaining subcellular membrane junctions [5].

Mutations in Jph3 have been linked to various disorders. In hepatocellular carcinoma (HCC), Jph3 exhibits low levels due to promoter methylation. Reducing its DNA methylation with 5-Aza-2'-deoxycytidine increases protein expression and inhibits the malignant biological behavior of HCC cells. Also, increasing Jph3 expression through gene regulation inhibits HCC cell proliferation, invasion, and migration, affecting epithelial-mesenchymal transition (EMT) [1]. In a five-generation African-American family, Jph3 repeat expansions caused a progressive akinetic-rigid syndrome with severe dementia and putaminal rim [2]. Moreover, Jph3 expansion mutations are common in South African patients with African ancestry and a Huntington disease phenotype, causing Huntington disease-like 2 (HDL2) [3]. In HDL2, Jph3 transcripts and full-length Jph3 protein are decreased, and Jph3 hemizygous and null mice exhibit abnormal motor function, suggesting that the pathogenic mechanism of HDL2 involves both a toxic gain of function of Jph3 RNA and a toxic loss of Jph3 expression [4].

In conclusion, Jph3 is crucial for maintaining subcellular membrane junctions and regulating neuronal calcium flux. Its dysregulation, often through methylation or repeat expansions, is associated with diseases like HCC and HDL2. The use of gene knockout mouse models, as in the study of HDL2, has provided insights into the role of Jph3 in disease pathogenesis, helping to understand the underlying mechanisms of these diseases.