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Title: Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish
Authors: Fasano, Giulia
Muto, Valentina
Radio, Francesca Clementina
Venditti, Martina
Mosaddeghzadeh, Niloufar
Coppola, Simona
Paradisi, Graziamaria
Zara, Erika
Bazgir, Farhad
Ziegler, Alban
Chillemi, Giovanni 
Bertuccini, Lucia
Tinari, Antonella
Vetro, Annalisa
Pantaleoni, Francesca
Pizzi, Simone
Conti, Libenzio Adrian
Petrini, Stefania
Bruselles, Alessandro
Prandi, Ingrid Guarnetti
Mancini, Cecilia
Chandramouli, Balasubramanian
Barth, Magalie
Bris, Céline
Milani, Donatella
Selicorni, Angelo
Macchiaiolo, Marina
Gonfiantini, Michaela V
Bartuli, Andrea
Mariani, Riccardo
Curry, Cynthia J
Guerrini, Renzo
Slavotinek, Anne
Iascone, Maria
Dallapiccola, Bruno
Ahmadian, Mohammad Reza
Lauri, Antonella
Tartaglia, Marco
Issue Date: 2022
Vesicle biogenesis, trafficking and signaling via Endoplasmic reticulum-Golgi network support essential developmental processes and their disruption lead to neurodevelopmental disorders and neurodegeneration. We report that de novo missense variants in ARF3, encoding a small GTPase regulating Golgi dynamics, cause a developmental disease in humans impairing nervous system and skeletal formation. Microcephaly-associated ARF3 variants affect residues within the guanine nucleotide binding pocket and variably perturb protein stability and GTP/GDP binding. Functional analysis demonstrates variably disruptive consequences of ARF3 variants on Golgi morphology, vesicles assembly and trafficking. Disease modeling in zebrafish validates further the dominant behavior of the mutants and their differential impact on brain and body plan formation, recapitulating the variable disease expression. In-depth in vivo analyses traces back impaired neural precursors' proliferation and planar cell polarity-dependent cell movements as the earliest detectable effects. Our findings document a key role of ARF3 in Golgi function and demonstrate its pleiotropic impact on development.
ISSN: 2041-1723
DOI: 10.1038/s41467-022-34354-x
Appears in Collections:A1. Articolo in rivista

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