Structure-Function of the Human WAC Protein in GABAergic Neurons: Towards an Understanding of Autosomal Dominant DeSanto-Shinawi Syndrome

Abstract

Dysfunction of the WW domain-containing adaptor with coiled-coil, WAC, gene underlies a rare autosomal dominant disorder, DeSanto-Shinawi syndrome (DESSH). DESSH is associated with facial dysmorphia, hypotonia, and cognitive alterations, including attention deficit hyperactivity disorder and autism. How the WAC protein localizes and functions in neural cells is critical to understanding its role during development. To understand the genotype-phenotype role of WAC, we developed a knowledgebase of WAC expression, evolution, human genomics, and structural/motif analysis combined with human protein domain deletions to assess how conserved domains guide cellular distribution. Then assessed in a cell type implicated in DESSH, cortical GABAergic neurons. WAC contains conserved charged amino acids, phosphorylation signals, and enriched nuclear motifs, suggesting a role in cellular signaling and gene transcription. Human DESSH variants are found within these regions. We also discovered and tested a nuclear localaization domain that impacts the cellular distribution of the protein. These data provide new insights into the potential roles of this critical developmental gene, establishing a platform to assess further translational studies, including the screening of missense genetic variants in WAC. Moreover, these studies are essential for understanding the role of human WAC variants in more diverse neurological phenotypes, including autism spectrum disorder.

Complimentary vertebrateWacmodels exhibit phenotypes relevant to DeSanto-Shinawi Syndrome

“…A multitude of cellular roles for WAC exist, including regulation of mammalian target of rapamycin (mTOR), mitosis, transcription and autophagy [7–10], likely through distinct protein/protein interactions of WAC in different cells and cellular compartments. A recent study assessed the role of various protein domains in the human WAC protein and isolated an amino terminal nuclear localization signal as well as a highly conserved disorganized region that contains several putative phosphorylation motifs that are mutated in humans with known Wac variants [11]. The functional role of these domains and of WAC itself are still poorly understood in vertebrates.…”