1. De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function
- Author
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Peter Bauer, Jonathan Baets, G. Bradley Schaefer, Wenting Guo, Tine Deconinck, Bo Sun, Katherine L. Helbig, Sha Tang, Pranoot Tanpaiboon, Erika Palmaer, Peter De Jonghe, Florian Harmuth, Ingeborg Krägeloh-Mann, Matthis Synofzik, Rebecca Schüle, Ruiwu Wang, S. R. Wayne Chen, Ludger Schöls, Stephan Züchner, and Janina Gburek-Augustat
- Subjects
0301 basic medicine ,Ataxia ,genetics [Inositol 1,4,5-Trisphosphate Receptors] ,Mutation, Missense ,Inositol 1,4,5-Trisphosphate ,medicine.disease_cause ,Article ,03 medical and health sciences ,0302 clinical medicine ,Loss of Function Mutation ,metabolism [Inositol 1,4,5-Trisphosphate] ,Genetics ,medicine ,Missense mutation ,Humans ,Inositol 1,4,5-Trisphosphate Receptors ,metabolism [Calcium] ,ddc:610 ,Child ,Gene ,Biology ,Genetics (clinical) ,Spinocerebellar Degenerations ,Mutation ,business.industry ,medicine.disease ,Phenotype ,metabolism [Inositol 1,4,5-Trisphosphate Receptors] ,genetics [Spinocerebellar Degenerations] ,ITPR1 protein, human ,3. Good health ,Chemistry ,030104 developmental biology ,HEK293 Cells ,pathology [Spinocerebellar Degenerations] ,Cohort ,Spinocerebellar ataxia ,Calcium ,Female ,Human medicine ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
We explored the clinico-genetic basis of spinocerebellar ataxia 29 (SCA29) by determining the frequency, phenotype, and functional impact of ITPR1 missense variants associated with early-onset ataxia (EOA). Three hundred thirty one patients from a European EOA target cohort (n = 120), US-American EOA validation cohort (n = 72), and early-onset epileptic encephalopathy (EOEE) control cohort (n = 139) were screened for de novo ITPR1 variants. The target cohort was also screened for inherited ITPR1 variants. The variants' functional impact was determined by IP3-induced Ca2+ release in HEK293 cells. 3/120 patients (2.5%) from the target cohort and 4/72 patients (5.5%) from the validation cohort, but none from the EOEE control cohort, carried de novo ITPR1 variants. However, most ITPR1 variants (7/10 = 70%) in the target cohort were inherited from a healthy parent, with 3/6 patients carrying disease-causing variants in other genes. This suggests limited or no phenotypic impact of many ITPR1 missense variants, even if ultra-rare and well-conserved. While common bioinformatics tools did not discriminate de novo from other ITPR1 variants, functional characterization demonstrated reduced IP3-induced Ca2+ release for all de novo variants, including the recurrent c.805C>T (p.(R269W)) variant. In sum, these findings show that de novo ITPR1 missense variants are a recurrent cause of EOA (SCA29) across independent cohorts, acting via loss of IP3 channel function. Inherited ITPR1 variants are also enriched in EOA, but often without strong impact, albeit rare and well-conserved. Functional studies allow identifying ITPR1 variants with large impact, likely disease-causing. Such functional confirmation is warranted for inherited ITPR1 variants before making a SCA29 diagnosis.
- Published
- 2018