title: A mutation in the human Uncoordinated 119 gene impairs TCR signaling and is associated with CD4 lymphopenia.
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.
authors.affiliation: Department of Medicine, Division of Allergy and Immunology, National Jewish Health,1400 Jackson St, Denver, CO 80206, USA. alamr@njhealth.org
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Gorska
authors.forename: Rafeul
authors.initials: R
authors.lastname: Alam
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D018791:CD4 Lymphocyte Count; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D018344:T-Lymphocytopenia, Idiopathic CD4-Positive / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D011948:Receptors, Antigen, T-Cell; C098032:UNC119 protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)