ITPR1 – Spinocerebellar Ataxia Type 15/16

Spinocerebellar ataxia type 15/16 (SCA15/16) is an adult‐onset, slowly progressive cerebellar ataxia characterized by gait instability, limb ataxia, dysarthria and nystagmus. The causative gene, ITPR1, encodes the inositol 1,4,5‐trisphosphate receptor type 1, a calcium channel highly expressed in Purkinje cells. Disease‐causing ITPR1 variants act predominantly via haploinsufficiency, leading to reduced IP₃‐mediated Ca²⁺ release and cerebellar degeneration.

Autosomal dominant inheritance is supported by numerous deletion and point mutation reports. A phenotypic review of 60 patients confirmed by multi‐exon ITPR1 deletions highlights gait ataxia (88.3%), dysarthria (75.0%), nystagmus (73.3%) and limb ataxia (71.7%) ([PMID:27908616]). Early mapping in two Japanese families and an Australian pedigree identified heterozygous deletions and a missense variant c.3248C>T (p.Pro1083Leu) segregating with disease ([PMID:18579805]).

Variant spectrum encompasses large deletions of exons 1–10, affecting haploinsufficiency, and rare truncating and missense alleles across functional domains. Recurrent losses of exons 1–10 have been detected in multiple families ([PMID:17590087]), while point mutations in the IRBIT binding and channel regions underscore domain-specific effects. The prototypical c.3248C>T (p.Pro1083Leu) variant illustrates conservation and pathogenicity in the coupling domain.

Functional studies strongly corroborate genetic findings. Heterozygous Itpr1(Δ18) mice exhibit progressive ataxia and Purkinje cell loss, mirroring human SCA15 ([PMID:17590087]). Drosophila expressing rat Itpr1 complements fly itpr mutants, restoring motor coordination and Ca²⁺ dynamics ([PMID:22817477]). These assays confirm haploinsufficiency as the primary mechanism of pathogenesis.

No conflicting evidence has challenged the ITPR1–SCA15/16 link. Family‐based segregation and functional models consistently demonstrate causality. Additional case reports of de novo and inherited missense variants expand the phenotype but do not weaken the core association.

In summary, ITPR1 haploinsufficiency due to deletions or point mutations definitively causes autosomal dominant SCA15/16. Genetic testing for multi‐exon deletions and key missense variants should be incorporated into diagnostic panels. Functional confirmation in cellular and animal models underpins clinical decision‐making and supports therapeutic targeting of calcium signaling.

References

• Neurologia i neurochirurgia polska • 2017 • Spinocerebellar ataxia 15: A phenotypic review and expansion. PMID:27908616
• Neurology • 2008 • Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families. PMID:18579805
• PLoS genetics • 2007 • Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PMID:17590087
• Journal of neurogenetics • 2012 • Functional complementation of Drosophila itpr mutants by rat Itpr1. PMID:22817477

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