Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish

• Published in: Nature communications Vol. 13; no. 1; p. 6841
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.11.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/2; 13/51; 14; 14/19; 14/28; 14/63; 42; 45/23; 59; 631/136/1425; 631/208/2489/144; 631/80/642/1525; 64/116; 692/699/375/366; ADP-Ribosylation Factors - metabolism; Animals; Binding; Biosynthesis; Cell division; Danio rerio; Disease; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Evolution; Functional analysis; Golgi apparatus; Golgi Apparatus - metabolism; Humanities and Social Sciences; Humans; Membranes; Microcephaly; Microencephaly; Morphology; multidisciplinary; Mutation; Nervous system; Neural stem cells; Neurodegeneration; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Neurodevelopmental Disorders - metabolism; Neurological diseases; Nucleotides; Pediatrics; Polarity; Proteins; Science; Science (multidisciplinary); Stability analysis; Zebrafish; Zebrafish - genetics; Zebrafish - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34354-x

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. Disruptions to the ER-Golgi network can lead to neurodevelopmental disorders, though our understanding of these Golgipathies remains incomplete. Here Lauri, Tartaglia and colleagues show that ARF3 mutations cause a rare pediatric neurological disorder and perform detailed molecular characterization in fish.