No abstract

Purpose Human serine/threonine kinase 4 (STK4) deficiency is a rare, autosomal recessive genetic disorder leading to combined immunodeficiency; however, the extent to which immune signaling and host defense are impaired is unclear. We assessed the functional consequences of a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C > T, p.Arg291*) identified in a pediatric patient by comparing his innate and adaptive cell-mediated and humoral immune responses with those of three heterozygous relatives and unrelated controls. Methods The genetic etiology was verified by whole genome and Sanger sequencing. STK4 gene and protein expression was measured by quantitative RT-PCR and immunoblotting, respectively. Cellular abnormalities were assessed by high-throughput RT-RCR, RNA-Seq, ELISA, and flow cytometry. Antibody responses were assessed by ELISA and phage immunoprecipitation-sequencing. Results The patient exhibited partial loss of STK4 expression and complete loss of STK4 function combined with recurrent viral and bacterial infections, notably persistent Epstein–Barr virus viremia and pulmonary tuberculosis. Cellular and molecular analyses revealed abnormal fractions of T cell subsets, plasmacytoid dendritic cells, and NK cells. The transcriptional responses of the patient’s whole blood and PBMC samples indicated dysregulated interferon signaling, impaired T cell immunity, and increased T cell apoptosis as well as impaired regulation of cytokine-induced adhesion and leukocyte chemotaxis genes. Nonetheless, the patient had detectable vaccine-specific antibodies and IgG responses to various pathogens, consistent with a normal CD19 + B cell fraction, albeit with a distinctive antibody repertoire, largely driven by herpes virus antigens. Conclusion Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells.

Purpose. Human serine/threonine kinase 4 (STK4) deficiency is a rare, autosomal recessive genetic disorder leading to combined immunodeficiency. The extent to which STK4 deficiency impairs immune signaling and host defenses is unclear. We assessed the functional consequences of a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C>T, p.Arg291*) found in a pediatric patient by comparing the patient’s innate and adaptive cell-mediated and humoral immune responses with those of three heterozygous relatives and unrelated controls.Methods. The genetic etiology was identified by whole genome sequencing and confirmed by Sanger sequencing. STK4 gene and protein expression was measured by quantitative RT-PCR and immunoblotting, respectively. Cellular abnormalities were assessed by high-throughput RT-RCR, RNA-Seq, ELISA and polychromatic flow cytometry. Finally, antibody responses were delinated by ELISA and phage immunoprecipitation-sequencing.Results. The affected patient exhibited partial loss of STK4 expression and complete loss of STK4 function. The patient suffered from recurrent viral and bacterial infections, most notably persistent Epstein-Barr virus viremia and pulmonary tuberculosis. Cellular and molecular analyses revealed abnormalities to the fractions of T-cell subsets, plasmacytoid dendritic cells, and NK cells. The transcriptional responses of the patient’s whole blood and PBMC samples were reminiscent of dysregulated interferon signaling, impaired T immunity and increased T-cell apoptosis. Nonetheless, the patient had detectable vaccine-specific antibodies and IgG responses to various pathogens, consistent with a normal CD19 + B-cell fraction, albeit with a distinctive antibody repertoire, largely driven by herpesvirus antigens.Conclusion. Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells.