title: STAT1 hyperphosphorylation and defective IL12R/IL23R signaling underlie defective immunity in autosomal dominant chronic mucocutaneous candidiasis.
abstract: We recently reported the genetic cause of autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) as a mutation in the STAT1 gene. In the present study we show that STAT1 Arg274Trp mutations in the coiled-coil (CC) domain is the genetic cause of AD-CMC in three families of patients. Cloning and transfection experiments demonstrate that mutated STAT1 inhibits IL12R/IL-23R signaling, with hyperphosphorylation of STAT1 as the likely underlying molecular mechanism. Inhibition of signaling through the receptors for IL-12 and IL-23 leads to strongly diminished Th1/Th17 responses and hence to increased susceptibility to fungal infections. The challenge for the future is to translate this knowledge into novel strategies for the treatment of this severe immunodeficiency.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Sanne P
authors.initials: SP
authors.lastname: Smeekens
authors.forename: Theo S
authors.initials: TS
authors.lastname: Plantinga
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.forename: Bas
authors.initials: B
authors.lastname: Heinhuis
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.forename: Andrew
authors.initials: A
authors.lastname: Gennery
authors.forename: Bart Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Desa
authors.initials: D
authors.lastname: Lilic
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D002178:Candidiasis, Chronic Mucocutaneous / Q000235:genetics* / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010766:Phosphorylation; D018123:Receptors, Interleukin / Q000378:metabolism*; D053707:Receptors, Interleukin-12 / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: C515500:IL23R protein, human; D020381:Interleukin-17; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma