title: Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma.
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 Ca(2+) entry. STIM1 mRNA splicing, protein production, and Ca(2+) 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.
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. miby769@rockefeller.edu
authors.forename: Minji
authors.initials: M
authors.lastname: Byun
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.forename: Virginie
authors.initials: V
authors.lastname: Lelarge
authors.forename: Sabine
authors.initials: S
authors.lastname: Plancoulaine
authors.forename: Ayse
authors.initials: A
authors.lastname: Palanduz
authors.forename: Leyla
authors.initials: L
authors.lastname: Telhan
authors.forename: Bertrand
authors.initials: B
authors.lastname: Boisson
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Scott
authors.initials: S
authors.lastname: Dewell
authors.forename: Connie
authors.initials: C
authors.lastname: Zhao
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
authors.forename: Stefan
authors.initials: S
authors.lastname: Feske
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D002118:Calcium / Q000276:immunology / Q000378:metabolism; D002675:Child, Preschool; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000276:immunology; D055106:Genome-Wide Association Study; D019288:Herpesvirus 8, Human; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000276:immunology; D022821:RNA Splice Sites / Q000235:genetics*; D012514:Sarcoma, Kaposi / Q000235:genetics* / Q000276:immunology / Q000821:virology; D000071737:Stromal Interaction Molecule 1; D014421:Turkey
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; D022821:RNA Splice Sites; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium