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J Intern Med. 2015 Aug;278(2):203-10. doi: 10.1111/joim.12351. Epub 2015 Mar 10.

A missense mutation underlies defective SOCS4 function in a family with autoimmunity.

Author information

1
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
2
Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
3
Department of Pediatric Hematology, Immunology and Infectious Disease, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
4
Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
5
Department of Pediatric Endocrinology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

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.

CONCLUSION:

We present a family with an autoimmune disorder, probably resulting from dysregulated immune responses due to mutations in SOCS4.

KEYWORDS:

EGF; SOCS4; autoimmunity; exome sequencing; interleukin-6

PMID:
25639832
DOI:
10.1111/joim.12351
[Indexed for MEDLINE]
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