Itpr3, encoding inositol 1,4,5-trisphosphate receptor type 3, is a caffeine-sensitive inositol 1,4,5-triphosphate (IP3) receptor. It releases calcium from the endoplasmic reticulum, playing a key role in intracellular calcium release and calcium homeostasis [1,3,6]. It is involved in pathways such as non-canonical NF-κB signaling [2]. It has significance in multiple biological processes and is associated with various diseases.

Dominant mutations in Itpr3 have been identified as causes of Charcot-Marie-Tooth disease. These mutations, like p.Val615Met, p.Arg2524Cys, and p.Thr1424Met, lead to demyelinating and axonal neuropathy with variable age of onset and severity. The p.Val615Met variant has a dominant-negative effect on inositol 1,4,5-trisphosphate receptor type 3 function, altering Ca2+-transients in patient fibroblasts [1,4,7]. In colorectal cancer, Itpr3 promotes liver-metastatic colonization by inducing the expression of RELB, and in bladder cancer, it acts as an oncogene, promoting tumor growth, metastasis, and maintaining cancer stemness through the NF-κB/CD44 pathway [2,5]. Also, de novo missense variants in Itpr3 can cause combined immunodeficiency by impairing T cell Ca2+ dynamics [6].

In conclusion, Itpr3 is crucial for intracellular calcium regulation. Studies on Itpr3-related genetic mutations in various diseases, especially Charcot-Marie-Tooth disease, colorectal cancer, bladder cancer, and combined immunodeficiency, have enhanced our understanding of the role of Itpr3 in disease pathogenesis. These findings may offer potential directions for disease diagnosis, treatment, and further research on the underlying molecular mechanisms.