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 is involved in pathways like non-canonical NF-κB signaling [2,3]. It has significance in multiple biological processes and diseases, with genetic models potentially useful for studying its functions.

Dominant mutations in Itpr3 cause Charcot-Marie-Tooth disease, with identified variants such as p.Val615Met, p.Arg2524Cys, and p.Thr1424Met, which show a dominant-negative effect on inositol 1,4,5-trisphosphate receptor type 3 function and are associated with demyelinating and axonal features in neuropathy [1,3,5,7]. In colorectal cancer, Itpr3 promotes liver-metastatic colonization through the ITPR3/calcium/RELB axis [2]. In pancreatic and bladder cancers, Itpr3 over-expression is associated with poor prognosis, and it acts as an oncogene in bladder cancer, promoting tumor growth, metastasis, and stemness [4,6]. A recurrent dominant Itpr3 variant also leads to a complex multisystemic disorder with immunodeficiency, affecting calcium homeostasis, mitochondrial function, and T-cell development [3,8]. Additionally, the Itpr3 gene haplotype is associated with cervical squamous cell carcinoma risk, and SMARCA4/2 loss affects Itpr3-mediated Ca2+ flux to mitochondria in ovarian and lung cancers [9,10].

In conclusion, Itpr3 is crucial for intracellular calcium regulation and is involved in multiple disease processes, including various neuropathies, cancers, and immunodeficiency disorders. Studies on Itpr3, especially through genetic models, help to understand the molecular mechanisms underlying these diseases, potentially paving the way for new diagnostic and therapeutic strategies.

References:

1. Rönkkö, Julius, Molchanova, Svetlana, Revah-Politi, Anya, Tyynismaa, Henna, Ylikallio, Emil. 2020. Dominant mutations in ITPR3 cause Charcot-Marie-Tooth disease. In Annals of clinical and translational neurology, 7, 1962-1972. doi:10.1002/acn3.51190. https://pubmed.ncbi.nlm.nih.gov/32949214/

2. Moy, Ryan H, Nguyen, Alexander, Loo, Jia Min, Tavazoie, Saeed, Tavazoie, Sohail F. 2022. Functional genetic screen identifies ITPR3/calcium/RELB axis as a driver of colorectal cancer metastatic liver colonization. In Developmental cell, 57, 1146-1159.e7. doi:10.1016/j.devcel.2022.04.010. https://pubmed.ncbi.nlm.nih.gov/35487218/

3. Molitor, Anne, Lederle, Alexandre, Radosavljevic, Mirjana, Bertoli-Avella, Aida, Bahram, Seiamak. 2024. A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease. In Science advances, 10, eado5545. doi:10.1126/sciadv.ado5545. https://pubmed.ncbi.nlm.nih.gov/39270020/

4. Zheng, Wangyang, Bai, Xue, Zhou, Yongxu, Xu, Yi, Cui, Yunfu. 2022. Transcriptional ITPR3 as potential targets and biomarkers for human pancreatic cancer. In Aging, 14, 4425-4444. doi:10.18632/aging.204080. https://pubmed.ncbi.nlm.nih.gov/35580861/

5. Cabello-Murgui, Javier, Jiménez-Jiménez, Jesús, Vílchez, Juan J, Sevilla, Teresa, Sivera, Rafael. 2024. ITPR3-associated neuropathy: Report of a further family with adult onset intermediate Charcot-Marie-Tooth disease. In European journal of neurology, 31, e16485. doi:10.1111/ene.16485. https://pubmed.ncbi.nlm.nih.gov/39287469/

6. Zhang, Mengzhao, Wang, Lu, Yue, Yangyang, Wang, Xinyang, Fan, Jinhai. 2021. ITPR3 facilitates tumor growth, metastasis and stemness by inducing the NF-ĸB/CD44 pathway in urinary bladder carcinoma. In Journal of experimental & clinical cancer research : CR, 40, 65. doi:10.1186/s13046-021-01866-1. https://pubmed.ncbi.nlm.nih.gov/33573671/

7. Beijer, Danique, Dohrn, Maike F, Rebelo, Adriana, Shy, Michael E, Zuchner, Stephan. . A recurrent missense variant in ITPR3 causes demyelinating Charcot-Marie-Tooth with variable severity. In Brain : a journal of neurology, 148, 227-237. doi:10.1093/brain/awae206. https://pubmed.ncbi.nlm.nih.gov/38938188/

8. Blanco, Elena, Camps, Carme, Bahal, Sameer, Dhalla, Fatima, Kreins, Alexandra Y. 2024. Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency. In The Journal of experimental medicine, 222, . doi:10.1084/jem.20220979. https://pubmed.ncbi.nlm.nih.gov/39560673/

9. Yang, Yuh-Cheng, Chang, Tzu-Yang, Chen, Tze-Chien, Chang, Shih-Chuan, Lee, Yann-Jinn. . ITPR3 gene haplotype is associated with cervical squamous cell carcinoma risk in Taiwanese women. In Oncotarget, 8, 10085-10090. doi:10.18632/oncotarget.14341. https://pubmed.ncbi.nlm.nih.gov/28036301/

10. Xue, Yibo, Morris, Jordan L, Yang, Kangning, Prudent, Julien, Huang, Sidong. 2021. SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca2+ flux to mitochondria. In Nature communications, 12, 5404. doi:10.1038/s41467-021-25260-9. https://pubmed.ncbi.nlm.nih.gov/34518526/