An in-vivo zebrafish model with cecr1b deficiency recapitulates human DADA2 phenotype

Deficiency of adenosine deaminase 2 (DADA2) is a rare and potentially lethal genetic disease caused by loss-of-function (LOF) mutations in the ADA2 gene. Patients affected by DADA2 display vasculitis, hemorrhagic strokes, pan-cytopenia, systemic inflammation, and immune dysregulation. Current therapies for DADA2 patients are mainly based on the administration of anti-TNF agents to counteract inflammation and allogeneic hematopoietic stem cell transplantation (HSCT) to correct the hematological defects. However, advances in therapeutical treatments are hampered by the poor knowledge of the pathogenetic mechanisms and the lack of an animal model, as rodents do not have an ADA2 orthologue. Zebrafish (Danio rerio) presents two ADA2 orthologues, cecr1a and cecr1b. A cecr1b-deficient zebrafish model developed two of the most common human phenotypes: intracranial bleeding and neutropenia. Moreover, cecr1b knock-down in zebrafish caused increased expression of the proinflammatory cytokines TNF and IL-1b. We successfully rescued neutropenia in the cecr1b loss-of-function model by administrating G-CSF, a current treatment of DADA2 patients. We are currently investigating whether cecr1b knock-down affects the survival of hematopoietic stem progenitor cells and their differentiation toward the neutrophil lineage. Our study will uncover the molecular and cellular mechanisms responsible for the defects caused by cecr1b depletion in the zebrafish to reveal new insights into DADA2 pathogenesis and find possible treatments for patients.