title: A missense mutation underlies defective SOCS4 function in a family with autoimmunity.
abstract: OBJECTIVE
  The aim of this study was to determine the genetic and immunological defects underlying familial manifestations of an autoimmune disorder.
  
  
  METHODS
  Whole-exome sequencing was performed on the index patient with various manifestations of autoimmunity, including hypothyroidism, vitiligo and alopecia. Peripheral blood mononuclear cells and DNA of family members were used for functional and genetic testing of the candidate variants obtained by Sanger sequencing.
  
  
  RESULTS
  Exome sequencing identified 233 rare, coding and nonsynonymous variants in the index patient; five were highly conserved and affect genes that have a possible role in autoimmunity. Only a heterozygous missense mutation in the suppressor of cytokine signalling 4 gene (SOCS4) cosegregated with the autoimmune disorder in the family. SOCS4 is a known inhibitor of epidermal growth factor (EGF) receptor signalling, and functional studies demonstrated specific upregulation of EGF-dependent immune stimulation in affected family members.
  
  
  CONCLUSIONS
  We present a family with an autoimmune disorder, probably resulting from dysregulated immune responses due to mutations in SOCS4.
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: P
authors: P
authors: Arts
authors: Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: T S
authors: TS
authors: Plantinga
authors: Department of Pediatric Hematology, Immunology and Infectious Disease, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: J M
authors: JM
authors: van den Berg
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: C
authors: C
authors: Gilissen
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors: J A
authors: JA
authors: Veltman
authors: Department of Pediatric Endocrinology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: A S
authors: AS
authors: van Trotsenburg
authors: Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: F L
authors: FL
authors: van de Veerdonk
authors: Department of Pediatric Hematology, Immunology and Infectious Disease, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: T W
authors: TW
authors: Kuijpers
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: A
authors: A
authors: Hoischen
authors: Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: M G
authors: MG
authors: Netea
mesh_terms: D015551:Autoimmunity / Q000235:genetics*; D002648:Child; D004247:DNA / Q000235:genetics*; D059472:Exome; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D050031:Hashimoto Disease / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D013967:Thyroiditis, Autoimmune
chemical_list: C473084:SOCS4 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D004247:DNA
keywords: EGF; SOCS4; autoimmunity; exome sequencing; interleukin-6