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      • Department of Molecular Biology and Genetics
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      Inherited Irak-4 deficiency in acute human Herpesvirus-6 encephalitis

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      Author(s)
      Tepe, Zeynep Güneş
      Yazıcı, Yılmaz Yücehan
      Tank, Umut
      Köse, Ladin Işık
      Özer, Murat
      Aytekin, Caner
      Belkaya, Serkan
      Date
      2022-10-07
      Source Title
      Journal of Clinical Immunology
      Print ISSN
      0271-9142
       
      1573-2592
       
      Publisher
      Springer
      Volume
      43
      Pages
      192 - 205
      Language
      English
      Type
      Article
      Item Usage Stats
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      Abstract
      Human herpesvirus-6 (HHV-6) infection can rarely cause life-threatening conditions, such as encephalitis, in otherwise healthy children, with unclear pathogenesis. We studied a child who presented with acute HHV-6 encephalitis at the age of 10 months and who was homozygous for a novel missense mutation in IRAK4, encoding interleukin-1 receptor-associated kinase 4, identified by whole-exome sequencing. We tested the damaging impact of this mutation in silico by molecular dynamics simulations and in vitro by biochemical and functional experiments utilizing cell lines and patient’s cells. We found that the mutation is severely hypomorphic, impairing both the expression and function of IRAK-4. Patient’s leukocytes had barely detectable levels of IRAK-4 and diminished anti-viral immune responses to various stimuli inducing different Toll-like receptors and cytosolic nucleic acid sensors. Overall, these findings suggest that acute HHV-6 encephalitis can result from inborn errors of immunity to virus. This study represents the first report of isolated acute HHV-6 infection causing encephalitis in an inherited primary immunodeficiency, notably autosomal recessive (AR) partial IRAK-4 deficiency, and the first report of AR IRAK-4 deficiency presenting with a severe viral disease, notably HHV-6 encephalitis upon an acute infection, thereby expanding the clinical spectrum of IRAK-4 deficiency.
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      http://hdl.handle.net/11693/111861
      Published Version (Please cite this version)
      https://doi.org/10.1007/s10875-022-01369-4
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