4.7 Article

Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma

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JOURNAL OF EXPERIMENTAL MEDICINE
卷 207, 期 11, 页码 2307-2312

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ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20101597

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资金

  1. Institut National de la Sante et de la Recherche Medicale, University Paris Descartes
  2. Rockefeller University Center for Clinical and Translational Science [5UL1RR024143-03]
  3. Rockefeller University
  4. St. Giles Foundation
  5. National Institutes of Health [AI066128]
  6. Cancer Research Institute
  7. Assistance Publique-Hopitaux de Paris

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Classic Kaposi sarcoma (KS) is exceedingly rare in children from the Mediterranean Basin, despite the high prevalence of human herpesvirus-8 (HHV-8) infection in this region. We hypothesized that rare single-gene inborn errors of immunity to HHV-8 may underlie classic KS in childhood. We investigated a child with no other unusually severe infectious or tumoral phenotype who died from disseminated KS at two years of age. Whole-exome sequencing in the patient revealed a homozygous splice-site mutation in STIM1, the gene encoding stromal interaction molecule 1, which regulates store-operated Ca2+ entry. STIM1 mRNA splicing, protein production, and Ca2+ influx were completely abolished in EBV-transformed B cell lines from the patient, but were rescued by the expression of wild-type STIM1. Based on the previous discovery of STIM1 deficiency in a single family with a severe T cell immunodeficiency and the much higher risk of KS in individuals with acquired T cell deficiencies, we conclude that STIM1 T cell deficiency precipitated the development of lethal KS in this child upon infection with HHV-8. Our report provides the first evidence that isolated classic KS in childhood may result from single-gene defects and provides proof-of-principle that whole-exome sequencing in single patients can decipher the genetic basis of rare inborn errors.

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