De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function

Matthis Synofzik, Katherine L. Helbig, Florian Harmuth, Tine Deconinck, Pranoot Tanpaiboon, Bo Sun, Wenting Guo, Ruiwu Wang, Erika Palmaer, Sha Tang, G. Bradley Schaefer, Janina Gburek-Augustat, Stephan L Zuchner, Ingeborg Krägeloh-Mann, Jonathan Baets, Peter de Jonghe, Peter Bauer, S. R.Wayne Chen, Ludger Schöls, Rebecca Schüle

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalEuropean Journal of Human Genetics
DOIs
StateAccepted/In press - Jun 20 2018

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Ataxia
Brain Diseases
HEK293 Cells
Computational Biology
Phenotype
Genes
Spinocerebellar Ataxia 29

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Synofzik, M., Helbig, K. L., Harmuth, F., Deconinck, T., Tanpaiboon, P., Sun, B., ... Schüle, R. (Accepted/In press). De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function. European Journal of Human Genetics, 1-12. https://doi.org/10.1038/s41431-018-0206-3

De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function. / Synofzik, Matthis; Helbig, Katherine L.; Harmuth, Florian; Deconinck, Tine; Tanpaiboon, Pranoot; Sun, Bo; Guo, Wenting; Wang, Ruiwu; Palmaer, Erika; Tang, Sha; Schaefer, G. Bradley; Gburek-Augustat, Janina; Zuchner, Stephan L; Krägeloh-Mann, Ingeborg; Baets, Jonathan; de Jonghe, Peter; Bauer, Peter; Chen, S. R.Wayne; Schöls, Ludger; Schüle, Rebecca.

In: European Journal of Human Genetics, 20.06.2018, p. 1-12.

Research output: Contribution to journalArticle

Synofzik, M, Helbig, KL, Harmuth, F, Deconinck, T, Tanpaiboon, P, Sun, B, Guo, W, Wang, R, Palmaer, E, Tang, S, Schaefer, GB, Gburek-Augustat, J, Zuchner, SL, Krägeloh-Mann, I, Baets, J, de Jonghe, P, Bauer, P, Chen, SRW, Schöls, L & Schüle, R 2018, 'De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function', European Journal of Human Genetics, pp. 1-12. https://doi.org/10.1038/s41431-018-0206-3
Synofzik, Matthis ; Helbig, Katherine L. ; Harmuth, Florian ; Deconinck, Tine ; Tanpaiboon, Pranoot ; Sun, Bo ; Guo, Wenting ; Wang, Ruiwu ; Palmaer, Erika ; Tang, Sha ; Schaefer, G. Bradley ; Gburek-Augustat, Janina ; Zuchner, Stephan L ; Krägeloh-Mann, Ingeborg ; Baets, Jonathan ; de Jonghe, Peter ; Bauer, Peter ; Chen, S. R.Wayne ; Schöls, Ludger ; Schüle, Rebecca. / De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function. In: European Journal of Human Genetics. 2018 ; pp. 1-12.
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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.",
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AU - Synofzik, Matthis

AU - Helbig, Katherine L.

AU - Harmuth, Florian

AU - Deconinck, Tine

AU - Tanpaiboon, Pranoot

AU - Sun, Bo

AU - Guo, Wenting

AU - Wang, Ruiwu

AU - Palmaer, Erika

AU - Tang, Sha

AU - Schaefer, G. Bradley

AU - Gburek-Augustat, Janina

AU - Zuchner, Stephan L

AU - Krägeloh-Mann, Ingeborg

AU - Baets, Jonathan

AU - de Jonghe, Peter

AU - Bauer, Peter

AU - Chen, S. R.Wayne

AU - Schöls, Ludger

AU - Schüle, Rebecca

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