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

Giulia Fasano, Valentina Muto, Francesca Clementina Radio, Martina Venditti, Niloufar Mosaddeghzadeh, Simona Coppola, Graziamaria Paradisi, Erika Zara, Farhad Bazgir, Alban Ziegler, Giovanni Chillemi, Lucia Bertuccini, Antonella Tinari, Annalisa Vetro, Francesca Pantaleoni, Simone Pizzi, Libenzio Adrian Conti, Stefania Petrini, Alessandro Bruselles, Ingrid Guarnetti Prandi, Cecilia Mancini, Balasubramanian Chandramouli, Magalie Barth, Céline Bris, Donatella Milani, Angelo Selicorni, Marina Macchiaiolo, Michaela V. Gonfiantini, Andrea Bartuli, Riccardo Mariani, Cynthia J. Curry, Renzo Guerrini, Anne Slavotinek, Maria Iascone, Bruno Dallapiccola, Mohammad Reza Ahmadian, Antonella Lauri () and Marco Tartaglia ()
Additional contact information
Giulia Fasano: IRCCS
Valentina Muto: IRCCS
Francesca Clementina Radio: IRCCS
Martina Venditti: IRCCS
Niloufar Mosaddeghzadeh: Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf
Simona Coppola: Istituto Superiore di Sanità
Graziamaria Paradisi: IRCCS
Erika Zara: IRCCS
Farhad Bazgir: Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf
Alban Ziegler: SFR ICAT
Giovanni Chillemi: University of Tuscia
Lucia Bertuccini: Istituto Superiore di Sanità
Antonella Tinari: Istituto Superiore di Sanità
Annalisa Vetro: University of Florence
Francesca Pantaleoni: IRCCS
Simone Pizzi: IRCCS
Libenzio Adrian Conti: IRCCS
Stefania Petrini: IRCCS
Alessandro Bruselles: Istituto Superiore di Sanità
Ingrid Guarnetti Prandi: University of Tuscia
Cecilia Mancini: IRCCS
Balasubramanian Chandramouli: CINECA
Magalie Barth: CHU d’Angers
Céline Bris: SFR ICAT
Donatella Milani: Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico
Angelo Selicorni: Azienda Socio Sanitaria Territoriale Lariana
Marina Macchiaiolo: IRCCS
Michaela V. Gonfiantini: IRCCS
Andrea Bartuli: IRCCS
Riccardo Mariani: IRCCS
Cynthia J. Curry: University of California San Francisco, Ca, Fresno, Ca
Renzo Guerrini: University of Florence
Anne Slavotinek: University of California San Francisco, Ca, Fresno, Ca
Maria Iascone: ASST Papa Giovanni XXIII
Bruno Dallapiccola: IRCCS
Mohammad Reza Ahmadian: Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf
Antonella Lauri: IRCCS
Marco Tartaglia: IRCCS

Nature Communications, 2022, vol. 13, issue 1, 1-29

Abstract: Abstract 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.

Date: 2022
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Citations: View citations in EconPapers (2)

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DOI: 10.1038/s41467-022-34354-x

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