Relevance to Autism

ECPAS was identified as an ASD candidate gene based on having a p-value < 0.001 following DeNovoWEST analysis of de novo variants in 16,877 ASD trios from the Simons Simplex Collection, the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; among the de novo variants observed in ASD cases in this analysis were four de novo loss-of-function variants and one damaging de novo missense variant (defined as having a REVEL score > 0.5). Subsequent gene-based meta-analysis involving de novo variant enrichment, transmission disequilibrium testing (TDT) of rare, inherited LoFs from unaffected parents to affected offspring, and comparisons of loss-of-function variants in cases vs population controls in this report found that ECPAS exhibited a nominal enrichment of loss-of-function variants in cases vs. controls (p = 0.02).

Molecular Function

Enables proteasome binding activity. Involved in ubiquitin-dependent ERAD pathway. Located in several cellular components, including centrosome; cytoplasmic vesicle; and nucleoplasm. Knockout of ECPAS in mice resulted in an increase in the density of NKCC1 protein in the axon initial segment (AIS) region, a change that positively correlates with a delay in the GABAergic response switch, as well as increased firing frequency of action potentials at early postnatal ages, hypersusceptibility to chemically induced convulsive seizures, and accelerated AIS developmental positioning, reflecting a perturbed AIS morphological plastic response to hyperexcitability arising from proteasome inhibition, a phenotype rescued by ectopic Ecm29 expression or NKCC1 inhibition.(Lee et al., 2020).

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