Detailed analysis of ITPR1 missense variants guides diagnostics and therapeutic design

Jussi Pekka Tolonen, Ricardo Parolin Schnekenberg, Simon McGowan, David Sims, Meriel McEntagart, Frances Elmslie, Debbie Shears, Helen Stewart, George K. Tofaris, Tabib Dabir, Patrick J. Morrison, Diana Johnson, Marios Hadjivassiliou, Sian Ellard, Charles Shaw‐Smith, Anna Znaczko, Abhijit Dixit, Mohnish Suri, Ajoy Sarkar, Rachel E. HarrisonGabriela Jones, Henry Houlden, Giorgia Ceravolo, Joanna Jarvis, Jonathan Williams, Morag E. Shanks, Penny Clouston, Julia Rankin, Lubov Blumkin, Tally Lerman‐Sagie, Penina Ponger, Salmo Raskin, Katariina Granath, Johanna Uusimaa, Hector Conti, Emma McCann, Shelagh Joss, Alexander J.M. Blakes, Kay Metcalfe, Helen Kingston, Marta Bertoli, Rachel Kneen, Sally Ann Lynch, Inmaculada Martínez Albaladejo, Austen Peter Moore, Wendy D. Jones, Esther B.E. Becker, Andrea H. Németh*, Genomics England Research Consortium

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
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The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3) receptor type 1 (IP3R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood.

We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy.

Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction.

We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3-binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype–phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression.

This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies.
Original languageEnglish
Pages (from-to)141-151
Number of pages11
JournalMovement Disorders
Issue number1
Early online date14 Nov 2023
Publication statusPublished - Jan 2024


  • cerebellum
  • IP3R1
  • ITPR1
  • Gillespie syndrome
  • next‐generation sequencing
  • spinocerebellar ataxia type 29


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