ITPR1 – Spinocerebellar Ataxia Type 29

ITPR1 encodes the inositol 1,4,5-trisphosphate receptor type 1, a ligand-gated Ca²⁺ channel highly expressed in cerebellar Purkinje cells. Heterozygous variants in ITPR1 cause spinocerebellar ataxia type 29 (SCA29; MONDO:0007298), an autosomal dominant congenital non-progressive ataxia characterized by infantile hypotonia, delayed motor milestones, gait ataxia and cognitive impairment.

Genetic evidence derives from multiple independent reports: a retrospective series of 21 individuals from 15 unrelated families with ITPR1 variants ([PMID:28659154]); a three-generation Chinese family with four affected individuals carrying a splice mutation c.1207-2A>T ([PMID:29196976]); a Māori kindred with two affected siblings harboring c.800C>T (p.Thr267Met) ([PMID:31632679]); and a de novo c.800C>T (p.Thr267Met) in a Korean patient ([PMID:38860480]). In total, at least 28 probands across 18 families exhibit autosomal dominant inheritance and segregation of pathogenic missense and splice variants.

The variant spectrum is dominated by missense changes clustered in the IP₃-binding core and channel domains, with one recurrent hotspot c.800C>T (p.Thr267Met). Additional pathogenic alleles include splice site mutations (e.g., c.1207-2A>T) and rare in-frame deletions. No common founder effect has been identified beyond the p.Thr267Met hotspot.

Functional assays demonstrate that de novo ITPR1 missense variants markedly reduce IP₃-induced Ca²⁺ release in HEK293 cells, confirming a loss-of-function mechanism consistent with cerebellar dysfunction ([PMID:29925855]). Animal and cellular models further support that disrupted ITPR1-mediated Ca²⁺ signaling underlies the SCA29 phenotype.

No conflicting reports have disputed the ITPR1–SCA29 association. The collective genetic and experimental data—spanning segregation in multi-generation families, consistent variant effects, and concordant functional impairment—fulfill strong ClinGen criteria for a gene-disease link.

Key take-home sentence: Heterozygous ITPR1 missense and splice variants cause autosomal dominant SCA29 via disrupted IP₃-mediated Ca²⁺ release, supporting targeted genetic testing for early diagnosis and management.

References

• Orphanet journal of rare diseases • 2017 • Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia. PMID:28659154
• Cerebellum (London, England) • 2018 • Identification of a Splicing Mutation in ITPR1 via WES in a Chinese Early-Onset Spinocerebellar Ataxia Family. PMID:29196976
• Cerebellum & ataxias • 2019 • Spinocerebellar Ataxia type 29 in a family of Māori descent PMID:31632679
• Molecular genetics & genomic medicine • 2024 • Discovery of a de novo ITPR1 missense mutation in a patient with early-onset cerebellar ataxia: A rare case report of spinocerebellar ataxia 29. PMID:38860480
• European journal of human genetics : EJHG • 2018 • De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function. PMID:29925855

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