Relevance to Autism

Genetic association has been found between the ATP2B2 gene and autism in a combined AGRE, ISART (Italian) and US cohort (Carayol et al., 2011). A de novo missense variant that was predicted to be damaging (p.Thr818Met) was identified in the ATP2B2 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014, and two de novo nonsense variants in this gene were observed in ASD probands from Japanese trios in Takata et al., 2018. TADA analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified ATP2B2 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05). Functional analysis of the ASD-associated p.Thr818Met missense variant, which was originally identified in an SSC proband, in Drosophila in Marcogliese et al., 2022 demonstrated a loss-of-function effect (failure to reduce expected viability to the extent of corresponding reference allele upon ubiquitous overexpression; wing-specific overexpression of mutant ATP2B2 failed to induce the curled wing phenotype caused by overexpression of reference ATP2B2).

Molecular Function

This gene encodes the plasma membrane calcium ATPase isoform 2. The protein encoded by this gene belongs to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. These enzymes remove bivalent calcium ions from eukaryotic cells against very large concentration gradients and play a critical role in intracellular calcium homeostasis.

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Model Summary

Importance of PMCA2 in calcium signaling, glutamate receptor expression and survival of Purkinje cells.

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