title: Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome.
abstract: Primary immunodeficiencies (PIDs) represent exquisite models for studying mechanisms of human host defense. In this study, we report on two unrelated kindreds, with two patients each, who had cryptosporidial infections associated with chronic cholangitis and liver disease. Using exome and candidate gene sequencing, we identified two distinct homozygous loss-of-function mutations in the interleukin-21 receptor gene (IL21R; c.G602T, p.Arg201Leu and c.240_245delCTGCCA, p.C81_H82del). The IL-21R(Arg201Leu) mutation causes aberrant trafficking of the IL-21R to the plasma membrane, abrogates IL-21 ligand binding, and leads to defective phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5. We observed impaired IL-21-induced proliferation and immunoglobulin class-switching in B cells, cytokine production in T cells, and NK cell cytotoxicity. Our study indicates that human IL-21R deficiency causes an immunodeficiency and highlights the need for early diagnosis and allogeneic hematopoietic stem cell transplantation in affected children.
authors: Department of Pediatric Hematology/Oncology, Hannover Medical School, 30625 Hannover, Germany.
authors: Daniel
authors: D
authors: Kotlarz
authors: Natalia
authors: N
authors: Ziętara
authors: Gulbu
authors: G
authors: Uzel
authors: Thomas
authors: T
authors: Weidemann
authors: Christian J
authors: CJ
authors: Braun
authors: Jana
authors: J
authors: Diestelhorst
authors: Peter M
authors: PM
authors: Krawitz
authors: Peter N
authors: PN
authors: Robinson
authors: Jochen
authors: J
authors: Hecht
authors: Jacek
authors: J
authors: Puchałka
authors: E Michael
authors: EM
authors: Gertz
authors: Alejandro A
authors: AA
authors: Schäffer
authors: Monica G
authors: MG
authors: Lawrence
authors: Lela
authors: L
authors: Kardava
authors: Dietmar
authors: D
authors: Pfeifer
authors: Ulrich
authors: U
authors: Baumann
authors: Eva-Doreen
authors: ED
authors: Pfister
authors: Eric P
authors: EP
authors: Hanson
authors: Axel
authors: A
authors: Schambach
authors: Roland
authors: R
authors: Jacobs
authors: Hans
authors: H
authors: Kreipe
authors: Susan
authors: S
authors: Moir
authors: Joshua D
authors: JD
authors: Milner
authors: Petra
authors: P
authors: Schwille
authors: Stefan
authors: S
authors: Mundlos
authors: Christoph
authors: C
authors: Klein
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D053738:Interleukin-21 Receptor alpha Subunit / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D009154:Mutation; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C508117:IL21R protein, human; D053738:Interleukin-21 Receptor alpha Subunit; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human