Herpes simplex encephalitis due to a mutation in an E3 ubiquitin ligase

Stéphanie Bibert, Mathieu Quinodoz, Sylvain Perriot, Fanny S. Krebs, Maxime Jan, Rita C. Malta, Emilie Collinet, Mathieu Canales, Amandine Mathias, Nicole Faignart, Eliane Roulet-Perez, Pascal Meylan, René Brouillet, Onya Opota, Leyder Lozano-Calderon, Florence Fellmann, Nicolas Guex, Vincent Zoete, Sandra Asner, Carlo Rivolta, Renaud Pasquier and Pierre-Yves Bochud ()
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Stéphanie Bibert: University Hospital and University of Lausanne
Mathieu Quinodoz: Institute of Molecular and Clinical Ophthalmology Basel (IOB)
Sylvain Perriot: University Hospital and University of Lausanne
Fanny S. Krebs: University of Lausanne
Maxime Jan: University of Lausanne
Rita C. Malta: University Hospital and University of Lausanne
Emilie Collinet: University Hospital and University of Lausanne
Mathieu Canales: University Hospital and University of Lausanne
Amandine Mathias: University Hospital and University of Lausanne
Nicole Faignart: University Hospital and University of Lausanne
Eliane Roulet-Perez: University Hospital and University of Lausanne
Pascal Meylan: University Hospital and University of Lausanne
René Brouillet: University Hospital and University of Lausanne
Onya Opota: University Hospital and University of Lausanne
Leyder Lozano-Calderon: University Hospital and University of Lausanne
Florence Fellmann: University of Lausanne
Nicolas Guex: University of Lausanne
Vincent Zoete: University of Lausanne
Sandra Asner: University Hospital and University of Lausanne
Carlo Rivolta: Institute of Molecular and Clinical Ophthalmology Basel (IOB)
Renaud Pasquier: University Hospital and University of Lausanne
Pierre-Yves Bochud: University Hospital and University of Lausanne

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Encephalitis is a rare and potentially fatal manifestation of herpes simplex type 1 infection. Following genome-wide genetic analyses, we identified a previously uncharacterized and very rare heterozygous variant in the E3 ubiquitin ligase WWP2, in a 14-month-old girl with herpes simplex encephalitis. The p.R841H variant (NM_007014.4:c.2522G > A) impaired TLR3 mediated signaling in inducible pluripotent stem cells-derived neural precursor cells and neurons; cells bearing this mutation were also more susceptible to HSV-1 infection compared to control cells. The p.R841H variant increased TRIF ubiquitination in vitro. Antiviral immunity was rescued following the correction of p.R841H by CRISPR-Cas9 technology. Moreover, the introduction of p.R841H in wild type cells reduced such immunity, suggesting that this mutation is linked to the observed phenotypes.

Date: 2024
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DOI: 10.1038/s41467-024-48287-0

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