ISGylation is disrupted by UBA7 gene variants identified in individuals with neurodevelopmental disorder phenotypes

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 K.

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 - Publisher Copyright: © 2026 The Author(s)

PY - 2026/5/15

Y1 - 2026/5/15

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 human homolog of ariadne (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 human homolog of ariadne (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 - Genetics

KW - Molecular biology

KW - Neuroscience

UR - https://www.scopus.com/pages/publications/105035496212

U2 - 10.1016/j.isci.2026.115454

DO - 10.1016/j.isci.2026.115454

M3 - Article

C2 - 42023152

AN - SCOPUS:105035496212

SN - 2589-0042

VL - 29

JO - iScience

JF - iScience

IS - 5

M1 - 115454

ER -