A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes

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.

A unique STK4 mutation truncating only the C-terminal SARAH domain results in a mild clinical phenotype despite severe T cell lymphopenia: Case report

“…are not a null phenotype). Previous mutations largely involved truncating or splice site changes that led to mRNA degradation and loss of detectable protein ( 6 , 7 , 11 , 14 , 17 ).…”

“…Additionally, as the literature indicates that STK4-deficient T cells show an exhausted phenotype prematurely (14), we also investigated this in our patient. T cells were stimulated for 2 days before assessing the helper T cell fraction for expression of PD-1, a surface marker for cellular exhaustion.…”

The TRIM37 variants in Mulibrey nanism patients paralyze follicular helper T cell differentiation

“…1b). Interestingly, NT5E and STK4 deficiency in humans has been reported as associating with combined immunodeficiency and recurrent infections [34][35][36] .…”