TY - JOUR
T1 - ISGylation is disrupted by UBA7 gene variants identified in individuals with neurodevelopmental disorder phenotypes.
AU - Bandi, Venkateshwarlu
AU - Venema, Myrrhe
AU - Wallace, Iona
AU - Mol, Merel O.
AU - Nikoncuk, Anita
AU - Schot, Rachel
AU - van Slegtenhorst, Marjon
AU - Bijlsma, Emilia
AU - Khan, Amjad
AU - White, Susan M.
AU - Rius, Rocio
AU - Delatycki, Martin B.
AU - Narayanan, Vinodh
AU - Swatek, Kirby N.
AU - Barakat, Tahsin Stefan
AU - Bustos, Francisco
N1 - Funding: The Barakat lab was supported by the Netherlands Organisation for Scientific Research (ZonMw Vidi, grant 09150172110002). The Swatek lab is supported by the Medical Research Council (MC_UU_00038/8) and K.N.S. is a Lister Institute Prize Fellow. The Rare Disease Flagship acknowledges financial support from the Royal Children’s Hospital Foundation, the Murdoch Children’s Research Institute, Paula Fox, The Andrew and Geraldine Buxton Foundation and the Pierce Armstrong Foundation. Molecular graphics and analyses performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of
California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases.
PY - 2026/3/30
Y1 - 2026/3/30
N2 - ISGylation is a ubiquitin-like enzymatic cascade that transfers the small modifier ISG15 to lysine residues of protein substrates. ISGylation occurs in a three-step enzymatic cascade involving UBA7 (E1), UBE2L6 (E2), and HERC5, TRIM25 or HHARI (E3) enzymes. This mechanism regulates core cellular processes, but its role in neurodevelopmental disorders remains unclear. Here, we identified individuals with neurodevelopmental disorder phenotypes harboring biallelic UBA7 gene variants and assessed their functional effects. Truncating UBA7 variants result in loss of catalytic activity, protein stability and localization. In contrast, a missense variant drives no functional defects. Fibroblasts harboring the variant p.Lys709Serfs*45 had reduced UBA7 transcript and produced a truncated and unstable UBA7 protein. These fibroblasts were unable to induce ISGylation upon interferon beta treatment, indicating a dysfunctional ISGylation system. Together, our findings identify cellular mechanisms disrupted by UBA7 variants and lay the foundation for uncovering the role of the ISGylation system and UBA7 in neurodevelopment.
AB - ISGylation is a ubiquitin-like enzymatic cascade that transfers the small modifier ISG15 to lysine residues of protein substrates. ISGylation occurs in a three-step enzymatic cascade involving UBA7 (E1), UBE2L6 (E2), and HERC5, TRIM25 or HHARI (E3) enzymes. This mechanism regulates core cellular processes, but its role in neurodevelopmental disorders remains unclear. Here, we identified individuals with neurodevelopmental disorder phenotypes harboring biallelic UBA7 gene variants and assessed their functional effects. Truncating UBA7 variants result in loss of catalytic activity, protein stability and localization. In contrast, a missense variant drives no functional defects. Fibroblasts harboring the variant p.Lys709Serfs*45 had reduced UBA7 transcript and produced a truncated and unstable UBA7 protein. These fibroblasts were unable to induce ISGylation upon interferon beta treatment, indicating a dysfunctional ISGylation system. Together, our findings identify cellular mechanisms disrupted by UBA7 variants and lay the foundation for uncovering the role of the ISGylation system and UBA7 in neurodevelopment.
KW - UBA7
KW - UBE1L
KW - ISG15
KW - ISGylation
KW - E1
KW - Ubiquitin-type protein
KW - Neurodevelopmental disorders
KW - Intellectual disability
KW - Exome sequencing
U2 - 10.1016/j.isci.2026.115454
DO - 10.1016/j.isci.2026.115454
M3 - Article
SN - 2589-0042
VL - In Press
JO - iScience
JF - iScience
M1 - 115454
ER -