Wiskott-Aldrich Syndrome in four male siblings from a consanguineous family from Lebanon
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Academic Press Inc.
Abstract
Background: Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder (PID) characterized by microthrombocytopenia, bloody diarrhea, eczema, recurrent infections, and a high incidence of autoimmunity and malignancy. Objective: To investigate the mechanism of thrombocytopenia and infections in four boys of consanguineous parents from Lebanon. Methods: Patient gDNA was studied using Next Generation Sequencing and Sanger Sequencing. Protein expression was determined by immunoblotting, and mRNA expression by semi-quantitative RT-PCR. F-actin polymerization and cellular proliferation were assayed by flow cytometry. Results: We identified a threonine to a methionine change at position 45 (T45M) of the WAS protein (WASp) that abolished protein expression and disturbed F-actin polymerization and T cell proliferation, but not B cell proliferation. In addition, the levels of the WAS-interacting protein (WIP) were significantly decreased in the patients. Conclusion: The mutation identified severely destabilizes WASp and affects the downstream signaling events important for T cell function, but not B cell function. It was previously known that the stability of WASp depends on WIP. In this manuscript, we report that the stability of WIP also depends on WASp. Finally, it is important to suspect X-linked PIDs even in consanguineous families. Clinical implications: The patients are above the optimal age for transplant in WAS, and it is difficult to identify one or more donors for four patients, therefore, they represent ideal candidates for gene therapy or interleukin-2 therapy. © 2020 Elsevier Inc.
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Gene therapy, Hematopoietic stem cell transplantation, Immune cell function, Primary immunodeficiency disease, Wiskott-aldrich syndrome, f-actin polymerization, B-lymphocytes, Child, Child, preschool, Consanguinity, Humans, Lebanon, Male, Mutation, Siblings, T-lymphocytes, Wiskott-aldrich syndrome, Wiskott-aldrich syndrome protein, X-linked combined immunodeficiency diseases, Antibiotic agent, F actin, Genomic dna, Immunoglobulin, Iron, Messenger rna, Methionine, Nucleotide, Protein, Rna, Steroid, Taq polymerase, Threonine, Unclassified drug, Wiskott aldrich syndrome protein, Wiskott aldrich syndrome protein interacting protein, Was protein, human, Abdomen, Actin polymerization, Allele, Amino acid substitution, Animal cell, Article, B lymphocyte, Binding site, Cd3+ t lymphocyte, Cd4+ t lymphocyte, Cd8+ t lymphocyte, Cell function, Clinical article, Consanguineous marriage, Controlled study, Cousin, Dry skin, Ecchymosis, Eczema, Epistaxis, Erythrocyte count, Erythrocyte transfusion, Exon, Family history, Flow cytometry, Gene, Gene expression, Gene mutation, Genetic analysis, Genetic transcription, High throughput sequencing, Hospitalization, Housekeeping gene, Human, Human cell, Idiopathic thrombocytopenic purpura, Immune deficiency, Immunoblotting, Infection, Leukocyte count, Lymphocyte count, Lymphocyte proliferation, Lymphocytopenia, Mean platelet volume, Memory cell, Mouse, Multiple cycle treatment, Natural killer cell, Nonhuman, Parent, Peripheral blood mononuclear cell, Platelet count, Pneumonia, Preschool child, Priority journal, Protein expression, Protein stability, Pruritus, Real time polymerase chain reaction, Recurrent disease, Rna extraction, Sanger sequencing, School child, Sibling, Signal transduction, T lymphocyte, Thrombocytopenia, Tooth abscess, Upper respiratory tract infection, Wipf1 gene, Wiskott aldrich syndrome, X chromosome linked disorder, Case report, Genetics, Immunology, X linked severe combined immunodeficiency