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 IP-binding affinity than wild-type (WT) ITPR1 and drastically changed the property of the intracellular Ca 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 Ca release. This is the first gain-of-function mechanism to be associated with ITPR1-related SCA29, providing novel insights into how enhanced Ca release can also contribute to the pathogenesis of this neurological disorder.

Numerous proteome analyses have been conducted on the postsynaptic density (PSD), a protein condensate beneath the postsynaptic membrane of excitatory synapses. Each has identified several hundred to thousands of proteins. While proteins with predictable functions have been well studied, functionally uncharacterized proteins are mostly overlooked. In this study, we perform a meta-analysis of the 35 PSD proteome datasets, including 5,869 proteins, identifying 97 uncharacterized proteins that appeared in multiple datasets. We focus on the top-ranked protein, FAM81A, renamed DRACC1. DRACC1 is expressed in forebrain neurons and enriched at the synapse. DRACC1 interacts with PSD proteins, including PSD-95, SynGAP, and NMDA receptors, and promotes liquid-liquid phase separation of those proteins. Consistently, the downregulation of DRACC1 in neurons causes a decrease in the size of PSD-95 puncta and the frequency of neuronal firing. Our results characterize DRACC1 as a novel synaptic protein facilitating the assembly of proteins within PSD. It also indicates the effectiveness of a meta-analytic approach of existing proteome datasets in identifying uncharacterized proteins.

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