A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes
<h3>Purpose</h3><p dir="ltr">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 fun...
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2021
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| _version_ | 1864513555909312512 |
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| author | Andrea Guennoun (2632468) |
| author2 | Salim Bougarn (413372) Taushif Khan (691254) Rafah Mackeh (14151225) Mahbuba Rahman (198499) Fatima Al-Ali (14151237) Manar Ata (9046473) Waleed Aamer (14056969) Debra Prosser (14151240) Tanwir Habib (47644) Evonne Chin-Smith (14151243) Khawla Al-Darwish (14151246) Qian Zhang (49333) Alya Al-Shakaki (3158886) Amal Robay (3158892) Ronald G. Crystal (8813645) Khalid Fakhro (3441305) Amal Al-Naimi (14151249) Eman Al Maslamani (14151252) Amjad Tuffaha (13040260) Ibrahim Janahi (3744933) Mohammad Janahi (14151255) Donald R. Love (14151258) Mohammed Yousuf Karim (8602092) Bernice Lo (3441317) Amel Hassan (14151231) Mehdi Adeli (11855663) Nico Marr (349853) |
| author2_role | author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| author_facet | Andrea Guennoun (2632468) Salim Bougarn (413372) Taushif Khan (691254) Rafah Mackeh (14151225) Mahbuba Rahman (198499) Fatima Al-Ali (14151237) Manar Ata (9046473) Waleed Aamer (14056969) Debra Prosser (14151240) Tanwir Habib (47644) Evonne Chin-Smith (14151243) Khawla Al-Darwish (14151246) Qian Zhang (49333) Alya Al-Shakaki (3158886) Amal Robay (3158892) Ronald G. Crystal (8813645) Khalid Fakhro (3441305) Amal Al-Naimi (14151249) Eman Al Maslamani (14151252) Amjad Tuffaha (13040260) Ibrahim Janahi (3744933) Mohammad Janahi (14151255) Donald R. Love (14151258) Mohammed Yousuf Karim (8602092) Bernice Lo (3441317) Amel Hassan (14151231) Mehdi Adeli (11855663) Nico Marr (349853) |
| author_role | author |
| dc.creator.none.fl_str_mv | Andrea Guennoun (2632468) Salim Bougarn (413372) Taushif Khan (691254) Rafah Mackeh (14151225) Mahbuba Rahman (198499) Fatima Al-Ali (14151237) Manar Ata (9046473) Waleed Aamer (14056969) Debra Prosser (14151240) Tanwir Habib (47644) Evonne Chin-Smith (14151243) Khawla Al-Darwish (14151246) Qian Zhang (49333) Alya Al-Shakaki (3158886) Amal Robay (3158892) Ronald G. Crystal (8813645) Khalid Fakhro (3441305) Amal Al-Naimi (14151249) Eman Al Maslamani (14151252) Amjad Tuffaha (13040260) Ibrahim Janahi (3744933) Mohammad Janahi (14151255) Donald R. Love (14151258) Mohammed Yousuf Karim (8602092) Bernice Lo (3441317) Amel Hassan (14151231) Mehdi Adeli (11855663) Nico Marr (349853) |
| dc.date.none.fl_str_mv | 2021-08-24T06:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1007/s10875-021-01115-2 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/A_Novel_STK4_Mutation_Impairs_T_Cell_Immunity_Through_Dysregulation_of_Cytokine-Induced_Adhesion_and_Chemotaxis_Genes/21597348 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Immunology Human serine/threonine kinase 4 (STK4) deficiency Combined immunodeficiency T cell lymphopenia Interferon Antibody repertoire Transcriptomics |
| dc.title.none.fl_str_mv | A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Purpose</h3><p dir="ltr">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.</p><h3>Methods</h3><p dir="ltr">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.</p><h3>Results</h3><p dir="ltr">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.</p><h3>Conclusion</h3><p dir="ltr">Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Clinical Immunology<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1007/s10875-021-01115-2" target="_blank">http://dx.doi.org/10.1007/s10875-021-01115-2</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_163b352e910573379289da6a8cece43c |
| identifier_str_mv | 10.1007/s10875-021-01115-2 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/21597348 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis GenesAndrea Guennoun (2632468)Salim Bougarn (413372)Taushif Khan (691254)Rafah Mackeh (14151225)Mahbuba Rahman (198499)Fatima Al-Ali (14151237)Manar Ata (9046473)Waleed Aamer (14056969)Debra Prosser (14151240)Tanwir Habib (47644)Evonne Chin-Smith (14151243)Khawla Al-Darwish (14151246)Qian Zhang (49333)Alya Al-Shakaki (3158886)Amal Robay (3158892)Ronald G. Crystal (8813645)Khalid Fakhro (3441305)Amal Al-Naimi (14151249)Eman Al Maslamani (14151252)Amjad Tuffaha (13040260)Ibrahim Janahi (3744933)Mohammad Janahi (14151255)Donald R. Love (14151258)Mohammed Yousuf Karim (8602092)Bernice Lo (3441317)Amel Hassan (14151231)Mehdi Adeli (11855663)Nico Marr (349853)Biological sciencesGeneticsBiomedical and clinical sciencesClinical sciencesImmunologyHuman serine/threonine kinase 4 (STK4) deficiencyCombined immunodeficiencyT cell lymphopeniaInterferonAntibody repertoireTranscriptomics<h3>Purpose</h3><p dir="ltr">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.</p><h3>Methods</h3><p dir="ltr">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.</p><h3>Results</h3><p dir="ltr">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.</p><h3>Conclusion</h3><p dir="ltr">Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Clinical Immunology<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1007/s10875-021-01115-2" target="_blank">http://dx.doi.org/10.1007/s10875-021-01115-2</a></p>2021-08-24T06:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1007/s10875-021-01115-2https://figshare.com/articles/journal_contribution/A_Novel_STK4_Mutation_Impairs_T_Cell_Immunity_Through_Dysregulation_of_Cytokine-Induced_Adhesion_and_Chemotaxis_Genes/21597348CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/215973482021-08-24T06:00:00Z |
| spellingShingle | A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes Andrea Guennoun (2632468) Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Immunology Human serine/threonine kinase 4 (STK4) deficiency Combined immunodeficiency T cell lymphopenia Interferon Antibody repertoire Transcriptomics |
| status_str | publishedVersion |
| title | A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes |
| title_full | A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes |
| title_fullStr | A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes |
| title_full_unstemmed | A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes |
| title_short | A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes |
| title_sort | A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes |
| topic | Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Immunology Human serine/threonine kinase 4 (STK4) deficiency Combined immunodeficiency T cell lymphopenia Interferon Antibody repertoire Transcriptomics |