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.
Keywords: Calcium signaling; Gain-of-function; ITPR1; Inositol 1,4,5-trisphosphate receptor 1; Non-progressive spinocerebellar ataxia; Spinocerebellar ataxia 29; Whole exome sequencing.