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ELMO1 (Engulfment and Cell Motility1)  is a gene involved in regulating cell motility through the ELMO1-DOCK2-RAC complex. Contrary to DOCK2 (Dedicator of Cytokinesis 2) deficiency, which has been reported to be associated with immunodeficiency diseases, variants of  ELMO1  have been associated with autoimmune diseases, such as diabetes and rheumatoid arthritis (RA). To explore the function of  ELMO1  in immune cells and to verify the functions of novel  ELMO1  variants  in vivo , we established a zebrafish  elmo1  mutant model. Live imaging revealed that, similar to mammals, the motility of neutrophils and T-cells was largely attenuated in zebrafish mutants. Consequently, the response of neutrophils to injury or bacterial infection was significantly reduced in the mutants. Furthermore, the reduced mobility of neutrophils could be rescued by the expression of constitutively activated Rac proteins, suggesting that zebrafish  elmo1  mutant functions  via  a conserved mechanism. With this mutant, three novel human  ELMO1  variants were transiently and specifically expressed in zebrafish neutrophils. Two variants, p.E90K (c.268G&amp;gt;A) and p.D194G (c.581A&amp;gt;G), could efficiently recover the motility defect of neutrophils in the  elmo1  mutant; however, the p.R354X (c.1060C&amp;gt;T) variant failed to rescue the mutant. Based on those results, we identified that zebrafish  elmo1  plays conserved roles in cell motility, similar to higher vertebrates. Using the transient-expression assay, zebrafish  elmo1  mutants could serve as an effective model for human variant verification  in vivo .

Functional Verification of Novel ELMO1 Variants by Live Imaging in Zebrafish