Meeting Abstract
Autism Spectrum Disorder (ASD) is currently estimated to affect more than 1% of the world population. While behavioral deficits and symptoms such as epilepsy are well studied, gastrointestinal (GI) distress remains a commonly reported but poorly understood comorbidity. Recent advances in gene editing techniques have allowed us to capitalize on the genetic aspect of ASD; to determine mechanisms behind ASD related GI distress, we explore how mutations in genes with high autism relatedness impact GI function. Mutations in the high-confidence ASD gene SHANK3 are considered causal for Phelan-McDermid Syndrome (PMS), a form of ASD with associated GI distress. Using the zebrafish as a model system, we used CRISPR/Cas9 to introduce clinically relevant C-terminal frameshift mutations in shank3a and shank3b zebrafish paralogues. We found that these mutations produce significantly slower rates of peristaltic contractions with correspondingly prolonged digestive passage time. Rescue injections of mRNA encoding the longest human SHANK3 isoform into shank3 zebrafish mutants produced larvae with gastric emptying similar to WT, but with remaining deficits in posterior intestinal motility. Serotonin-positive enteroendocrine cells were significantly reduced in shank3 mutants while enteric neuron counts and overall structure of the digestive tract epithelium, including goblet cell number was unaffected in shank3 mutant larvae. By contrast, in adult shank3 mutants there was a significant increase in goblet cell counts, suggesting a possible secondary inflammation that progresses with time
