FUNCTIONAL INSIGHTS INTO HETEROZYGOUS <EM>ITPR1</EM> VARIANTS ASSOCIATED WITH ATAXIA AND MIOSIS

Variants in the ITPR1 gene, encoding the inositol 1,4,5-triphospate receptor type 1 (IP₃R1) regulating cerebellar calcium (Ca²⁺) signaling, are linked to spinocerebellar ataxia types 15 and 29 (SCA15, SCA29) and Gillespie syndrome. While commonly associated with ataxia, only two cases to date have reported the rare co-occurrence of ataxia and miosis. Yet, insight into the functional consequences of these variants is lacking, limiting our understanding of the clinical variability in ITPR1-related disorders.
Here, we describe a multigenerational family with non-progressive congenital ataxia and miosis carrying a novel heterozygous variant (c.7697T>C; p.Phe2566Ser) in the ITPR1 gene. This novel variant affects a highly conserved residue within the IP₃R1 channel linker domain. Structural protein modelling of the novel variant predicted disruption of critical intramolecular interactions involved in Ca²⁺ gating and Zn²⁺ coordination. Functional assays revealed that the novel and previously published ataxia-miosis variants consistently reduced IP₃- and thapsigargin- induced ER Ca²⁺ release.
In conclusion, we provide functional evidence of pathogenicity for all ITPR1 variants associated with ataxia and miosis. Despite affecting different protein domains, all converge on a shared pathogenic mechanism on impaired IP₃R1 Ca²⁺ gating dynamics that is different from previous published ITPR1 missense variants. This highlights how subtle IP₃R1 channel dysregulation can produce a distinct ocular-cerebellar phenotype.