A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes.
| Publication Type | Case Report |
| Authors | Guennoun A, Bougarn S, Khan T, Mackeh R, Rahman M, Al-Ali F, Ata M, Aamer W, Prosser D, Habib T, Chin-Smith E, Al-Darwish K, Zhang Q, Al-Shakaki A, Robay A, Crystal R, Fakhro K, Al-Naimi A, Al Maslamani E, Tuffaha A, Janahi I, Janahi M, Love D, Karim M, Lo B, Hassan A, Adeli M, Marr N |
| Journal | J Clin Immunol |
| Volume | 41 |
| Issue | 8 |
| Pagination | 1839-1852 |
| Date Published | 08/24/2021 |
| ISSN | 1573-2592 |
| Keywords | Immunologic Deficiency Syndromes, Intracellular Signaling Peptides and Proteins, Protein Serine-Threonine Kinases |
| 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. |
| DOI | 10.1007/s10875-021-01115-2 |
| PubMed ID | 34427831 |
| PubMed Central ID | PMC8604862 |