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

MM Gorska, R Alam - Blood, The Journal of the American …, 2012 - ashpublications.org
MM Gorska, R Alam
Blood, The Journal of the American Society of Hematology, 2012ashpublications.org
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 …
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.
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