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<p>We recently identified de novo missense variants affecting the small GTPase ARF3 as the cause of a disorder characterized by developmental delay/intellectual disability, microcephaly, brain atrophy, epilepsy and minor skeletal defects. In vitro and in vivo analyses documented impaired Golgi integrity, vesicle trafficking, and brain and body axes development. Here, we report clinical features of five additional patients and the functional characterization of three novel <i>ARF3</i> variants. Cell-based assays corroborate a deleterious, variant-specific effect on protein stability, GTP binding and Golgi morphology. Zebrafish models confirm the dominant behavior of the tested variants and their variable impact on development. ARF3 mutants significantly affected Golgi integrity in vivo as well as brain size, recapitulating patients’ microcephaly. These findings expand the ARF3-related Golgipathy mutational spectrum, strengthen previous observations linking variants with dominant negative behavior to a markedly severe phenotype, and underscore the specific vulnerability of the nervous system to ARF and Golgi dysfunction.</p>

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Newly identified ARF3 variants strengthen the causal link between Golgi fragmentation and brain malformations

  • 期刊论文

  • 发表日期：

    2026年1月8日

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  • Valentina Muto,
  • Giulia Fasano,
  • Francesca Clementina Radio,
  • Catia Pedalino,
  • Mattia Carvetta,
  • Simona Coppola,
  • Erika Zara,
  • Stefania Petrini,
  • Caroline Schluth-Bolard,
  • Claire Bilbault,
  • Salima El Chehadeh,
  • Bénédicte Gérard,
  • Anne de Saint-Martin,
  • Daniel C. Koboldt,
  • Emily Sites,
  • Cynthia Curry,
  • Theresia Herget,
  • Ann-Sophie Höing,
  • Leonie von Elsner,
  • Eileen Elizabeth Barr,
  • Ugur Hodoglugil,
  • Anne Slavotinek,
  • Marco Tartaglia,
  • Antonella Lauri

摘要

We recently identified de novo missense variants affecting the small GTPase ARF3 as the cause of a disorder characterized by developmental delay/intellectual disability, microcephaly, brain atrophy, epilepsy and minor skeletal defects. In vitro and in vivo analyses documented impaired Golgi integrity, vesicle trafficking, and brain and body axes development. Here, we report clinical features of five additional patients and the functional characterization of three novel ARF3 variants. Cell-based assays corroborate a deleterious, variant-specific effect on protein stability, GTP binding and Golgi morphology. Zebrafish models confirm the dominant behavior of the tested variants and their variable impact on development. ARF3 mutants significantly affected Golgi integrity in vivo as well as brain size, recapitulating patients’ microcephaly. These findings expand the ARF3-related Golgipathy mutational spectrum, strengthen previous observations linking variants with dominant negative behavior to a markedly severe phenotype, and underscore the specific vulnerability of the nervous system to ARF and Golgi dysfunction.