| Autor: |
Antonella Lauri, Simona Coppola, Renzo Guerrini, Alban Ziegler, Marco Tartaglia, Andrea Bartuli, Maria Iascone, Ingrid Guarnetti Prandi, Angelo Selicorni, Balasubramanian Chandramouli, Magalie Barth, Marina Macchiaiolo, Annalisa Vetro, Martina Venditti, Francesca Clementina Radio, Simone Pizzi, Valentina Muto, Bruno Dallapiccola, Giulia Fasano, Alessandro Bruselles, Michaela Veronika Gonfiantini, Francesca Pantaleoni, Libenzio Adrian Conti, Donatella Milani, Stefania Petrini, Anne Slavotinek, Giovanni Chillemi, Céline Bris |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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