Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design.
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Tolonen Jussi Pekka, Parolin Schnekenberg Ricardo, McGowan Simon, Sims David, McEntagart Meriel, Elmslie Frances, Shears Debbie, Stewart Helen, Tofaris George K, Dabir Tabib, Morrison Patrick J, Johnson Diana, Hadjivassiliou Marios, Ellard Sian, Shaw-Smith Charles, Znaczko Anna, Dixit Abhijit, Suri Mohnish, Sarkar Ajoy, Harrison Rachel E, Jones Gabriela, Houlden Henry, Ceravolo Giorgia, Jarvis Joanna, Williams Jonathan, Shanks Morag E, Clouston Penny, Rankin Julia, Blumkin Lubov, Lerman-Sagie Tally, Ponger Penina, Raskin Salmo, Granath Katariina, Uusimaa Johanna, Conti Hector, McCann Emma, Joss Shelagh, Blakes Alexander J M, Metcalfe Kay, Kingston Helen, Bertoli Marta, Kneen Rachel, Lynch Sally Ann, Martínez Albaladejo Inmaculada, Moore Austen Peter, Jones Wendy D, Genomics England Research Consortium, Becker Esther B E, Németh Andrea H
Аннотация
OBJECTIVES: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.