Itpr1, encoding the inositol 1,4,5-trisphosphate (IP3) receptor type 1 (IP3R1), is a crucial gene in intracellular calcium signaling, especially in cerebellar cells [1,5]. As an InsP3-gated calcium channel, it modulates intracellular Ca2+ release, which is vital for various biological processes like cell development, learning, and memory [4].

Pathogenic missense variants in Itpr1 are associated with congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), severe pontine/cerebellar hypoplasia, and 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 showed ataxia and aniridia, with disrupted iris and corneal tissues, indicating Itpr1's role in anterior eye segment formation [3]. Also, superior vermian and hemispheric cerebellar atrophy was identified in 83% of patients with causative Itpr1 variants, suggesting it as a hallmark for Itpr1-related disorders [5].

In conclusion, Itpr1 is essential for intracellular calcium signaling and plays a significant role in cerebellar function, craniofacial development, and anterior eye segment formation. Studies using gene-knockdown in zebrafish and gene-deficient mice have provided insights into the disease mechanisms associated with Itpr1 variants, such as spinocerebellar ataxias, Gillespie syndrome, and hemifacial microsomia [1,2,3,5].