Dominantly acting variants in ARF3 have disruptive consequences on Golgi integrity and cause microcephaly recapitulated in zebrafish

This is the authors' abstract. We don't add key points for this paper.

Vesicle biogenesis, trafficking and signaling via the ER-Golgi network support essential processes during development and their disruption can lead to neurodevelopmental disorders and neurodegeneration. We report that de novo missense variants in ARF3, encoding a small GTPase regulating Golgi structure and function, cause a neurodevelopmental disease showing microcephaly and progressive cortical atrophy, with microsomia and rib anomalies in severely affected subjects, suggesting a pleiotropic effect. All microcephaly-associated variants clustered in the guanine nucleotide binding pocket and perturbed the biochemical behavior of the protein by stabilizing it in a GTP-bound state. Functional analysis proved the disruptive consequences of the variants on Golgi integrity, and brain and body plan formation. In-depth analysis in zebrafish embryos expressing ARF3 mutants traced back the developmental alterations to defective gastrulation cell movements as the earliest detectable effect. Our findings document a role of ARF3 in Golgi homeostasis and demonstrate an obligate dependence for early development.