A mutation in the human Uncoordinated 119 gene impairs TCR signaling and is associated with CD4 lymphopenia

Blood. 2012 Feb 9;119(6):1399-406. doi: 10.1182/blood-2011-04-350686. Epub 2011 Dec 19.

Abstract

Idiopathic CD4 lymphopenia (ICL) is an immunodeficiency disorder of unclear etiology. Here we describe a heterozygous dominant-negative missense mutation (codon 22 GGC→GTC; V22G) of the signaling adaptor protein Uncoordinated 119 (Unc119) in an ICL patient. The patient is a 32-year-old female with < 300 CD4 T cells/μL and with a history of recurrent sinusitis/otitis media, frequent episodes of shingles, a widespread fungal nail infection, fungal dermatitis, oral herpetic lesions, and bronchiolitis obliterans organizing pneumonia after 2 episodes of bacterial pneumonia. The patient's cells have reduced response to TCR stimulation, with impairment in both localization and enzymatic activation of the lymphocyte-specific kinase (Lck) resulting in decreased cell proliferation. Transduction of the mutant Unc119 but not wild-type Unc119 into normal T cells reproduces the signaling and proliferation defects. The mutation disrupts the Unc119-Lck interaction which is normally needed for stimulation of the Lck catalytic activity by TCR. The mutant protein also causes mislocalization of Lck to Rab11(+) perinuclear endosomes. The mutation is not present in 2 other patients with ICL, patients with secondary CD4 lymphopenia or 60 healthy subjects. The V22G mutation of Unc119 represents a novel genetic defect in ICL.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adult
  • Animals
  • Blotting, Western
  • CD4 Lymphocyte Count
  • Cell Proliferation
  • Cells, Cultured
  • Female
  • Humans
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / immunology
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mutation, Missense*
  • Protein Binding
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction / immunology*
  • T-Lymphocytopenia, Idiopathic CD4-Positive / immunology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Receptors, Antigen, T-Cell
  • UNC119 protein, human
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)