A Novel Homozygous LCK Variant in the SH2 Domain: Understanding Null vs. Hypomorphic LCK Mutations and Immune Dysregulation

Background The lymphocyte-specific protein tyrosine kinase (LCK) is a critical proximal component of T cell receptor (TCR)–mediated signaling. LCK deficiency leads to combined immunodeficiency (CID), but patients with null versus hypomorphic mutations present with varying degrees of immune dysregulation, suggesting a differential impact of such mutations on T cell development and function. Although expressed by B and NK cells, how distinct LCK mutations affect their phenotype and functions and immune dysregulation is not well understood. Here, we report the immunological and clinical impact of novel null and previously described hypomorphic LCK mutations. Methods To determine the consequences of the novel LCK p.Gly190fs*31 variant, we performed mass cytometry (CyTOF)–based immune phenotypic and functional profiling of peripheral blood mononuclear cells. T cell proliferation responses and NK cell phenotype and function were also assessed. Results A novel homozygous variant in LCK (p.Gly190fs31) was identified in a child born to consanguineous parents, presenting with recurrent viral and fungal infections. The immunological phenotype included T lymphopenia with a skewed memory phenotype, decreased T cell proliferation to PHA and absent to anti-CD3 stimulation, decreased isotype-switched B cells and concomitant hypogammaglobulinemia. p.Gly190fs31 variant led to nonsense-mediated mRNA decay, absent protein expression, and impaired LCK-mediated TCR signal transduction. Similarly to the previously described homozygous null p.C465R and hypomorphic P440S mutations, surface CD4 expression was diminished in the patients and heterozygous parents (and CD8 to a lesser extent). Additionally, CD21lo B cells were expanded in the P440S patient only, which has been associated with other monogenic disorders of immune dysregulation. Further, NK cell function was affected in patients with null mutations only, suggesting the more severe phenotype can be attributed to T and NK cell dysfunction while in the hypomorphic mutation T cell defects dominate microbial susceptibility risk. Conclusions Our results shed light on the LCK-mediated signaling threshold requirement for T, B, and NK cell development and differentiation—and most importantly, downstream immune dysregulation complications. These data could be leveraged to identify null vs. hypomorphic defects in rare CID/immune dysregulation due to proximal TCR signaling and to design chimeric antigen receptor cellular therapies applicable to autoimmune disorders and malignancies.