Itpr1, encoding the inositol 1,4,5-trisphosphate (IP3) receptor type 1 (IP3R1), is a crucial calcium ion channel involved in cerebellar intracellular calcium signaling [1,2,4]. It mediates calcium release from the endoplasmic reticulum and is essential for multiple biological processes, including craniofacial development, and is associated with various pathways related to cell function and development [1,2].

Pathogenic missense variants in Itpr1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), severe pontine/cerebellar hypoplasia, and may contribute to hemifacial microsomia spectrum [1,2]. In zebrafish, knockdown of itpr1b (homologous to human Itpr1) led to decreased craniofacial skeleton formation, highlighting its role in craniofacial development [2]. Mice lacking seven base pairs of the last Itpr1 exon exhibited ataxia and aniridia, with disrupted iris and corneal tissues, suggesting Itpr1's role in anterior eye segment formation [3].

In conclusion, Itpr1 is vital for intracellular calcium signaling and plays significant roles in craniofacial and anterior eye segment development. Its dysregulation, as revealed by loss-of-function studies in zebrafish and mouse models, is associated with multiple neurological and craniofacial disorders, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Tolonen, Jussi Pekka, Parolin Schnekenberg, Ricardo, McGowan, Simon, Becker, Esther B E, Németh, Andrea H. 2023. Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design. In Movement disorders : official journal of the Movement Disorder Society, 39, 141-151. doi:10.1002/mds.29651. https://pubmed.ncbi.nlm.nih.gov/37964426/

2. Liu, Zhixu, Sun, Hao, Dai, Jiewen, Sun, Jian, Wang, Xudong. 2021. ITPR1 Mutation Contributes to Hemifacial Microsomia Spectrum. In Frontiers in genetics, 12, 616329. doi:10.3389/fgene.2021.616329. https://pubmed.ncbi.nlm.nih.gov/33747042/

3. Kinoshita, Akira, Ohyama, Kaname, Tanimura, Susumu, Saitoh, Shinji, Yoshiura, Koh-Ichiro. 2021. Itpr1 regulates the formation of anterior eye segment tissues derived from neural crest cells. In Development (Cambridge, England), 148, . doi:10.1242/dev.188755. https://pubmed.ncbi.nlm.nih.gov/34338282/

4. Chesneau, Bertrand, Calvas, Patrick, Cassagne, Myriam, Fares-Taie, Lucas, Plaisancié, Julie. 2024. ITPR1: The missing gene in miosis-ataxia syndrome? In American journal of medical genetics. Part A, 194, e63655. doi:10.1002/ajmg.a.63655. https://pubmed.ncbi.nlm.nih.gov/38711238/