Abstract
We report three affected members, a mother and her two children, of a non-consanguineous Irish family who presented with a suspected autosomal dominant spinocerebellar ataxia characterized by early motor delay, poor coordination, gait ataxia, and dysarthria. Whole exome sequencing identified a novel missense variant (c.106C>T; p.[Arg36Cys]) in the suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor gene (ITPR1) as the cause of the disorder, resulting in a molecular diagnosis of spinocerebellar ataxia type 29. In the absence of grandparental DNA, microsatellite genotyping of healthy family members was used to confirm the de novo status of the ITPR1 variant in the affected mother, which supported pathogenicity. The Arg36Cys variant exhibited a significantly higher IP3-binding affinity than wild-type (WT) ITPR1 and drastically changed the property of the intracellular Ca2+ signal from a transient to a sigmoidal pattern, supporting a gain-of-function disease mechanism. To date, ITPR1 mutation has been associated with a loss-of-function effect, likely due to reduced Ca2+ release. This is the first gain-of-function mechanism to be associated with ITPR1-related SCA29, providing novel insights into how enhanced Ca2+ release can also contribute to the pathogenesis of this neurological disorder.
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Acknowledgements
We sincerely thank the family involved for their significant contribution to research and the use of genetic samples and clinical information. This work was supported by a Medical Research Charities Group Grant (to S.A.L. and J.P.C.) from the Health Research Board (MRCG/2013/02) and the Children’s Fund for Health, The Fundraising Office for Temple Street Children’s University Hospital, Dublin, Ireland (MRCG/2013/02). Jillian Casey is supported by a Medical Research Charities Group Grant (MRCG/2013/02). Functional studies were supported by Grant-in-Aid for Scientific Research (S) Grant Number 25221002 (to K.M) and Grant-in-Aid for Scientific Research (C) Grant Number 15K06761 (to C.H). We are grateful to the Support Unit for Bio-Material Analysis, RIKEN BSI Research Resources Center, for technical help with plasmid sequence analysis.
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This study was approved by the appropriate ethics committee and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.
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Casey, J.P., Hirouchi, T., Hisatsune, C. et al. A novel gain-of-function mutation in the ITPR1 suppressor domain causes spinocerebellar ataxia with altered Ca2+ signal patterns. J Neurol 264, 1444–1453 (2017). https://doi.org/10.1007/s00415-017-8545-5
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DOI: https://doi.org/10.1007/s00415-017-8545-5