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

Minji Byun, Avinash Abhyankar, Virginie Lelarge, Sabine Plancoulaine, Ayse Palanduz, Leyla Telhan, Bertrand Boisson, Capucine Picard, Scott Dewell, Connie Zhao, Emmanuelle Jouanguy, Stefan Feske, Laurent Abel, Jean Laurent Casanova

Research output: Contribution to journalArticlepeer-review

240 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2307-2312
Number of pages6
JournalJournal of Experimental Medicine
Volume207
Issue number11
DOIs
StatePublished - 25 Oct 2010
Externally publishedYes

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