Deficiency of Werner RecQ-type DNA helicase causes premature malnutrition in zebrafish

Werner syndrome is a genetic progeria characterized by premature aging symptoms, but its early-onset pathology remains unclear. We generated wrn truncation mutant (wrn ^-/-) zebrafish using CRISPR/Cas9 and identified two premature mortality phases: 7-21 and 60-90 days post-fertilization (dpf). Time-course transcriptomics revealed two wrn ^-/- subgroups. One showed the reduced expression of intestinal and pancreatic exocrine genes at 7-9 dpf, while the other maintained normal expression initially but eventually showed reduced pancreatic exocrine genes by 21-35 dpf. The prematurely dying wrn ^-/- larvae exhibited intestinal villi and pancreatic defects, along with DNA damage, cell-cycle arrest, and apoptosis. They also had lower glycogen, glucose, and fat levels compared to wild-type and late-dying wrn ^-/- larvae, suggesting malnutrition. Notably, excess feeding partially improved their survival. These findings reveal early pathological features in the zebrafish model of Werner syndrome.