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. © 2012 by The American Society of Hematology.