Wiskott-Aldrich Syndrome in four male siblings from a consanguineous family from Lebanon.

Rana Mansour, Youmna El-Orfali, Antoine Saber, Dolly Noun, Nour Youssef, Yolla Youssef, Rima Hanna-Wakim, Ghassan Dbaibo, Miguel Abboud, Michel J Massaad

Journal: Clinical immunology (Orlando, Fla.) 2021;219():108573

PMID: 32814211

Full Text on Elsevier Science View on PubMed

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.

Address: Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.; Division of Pediatric Hematology Oncology, Department of Pediatrics and Adolescent Medicine, Beirut, Lebanon; Children's Cancer Center of Lebanon, American University of Beirut Medical Center, Beirut, Lebanon.; Division of Pediatric Infectious Diseases, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon.; Division of Pediatric Infectious Diseases, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon.; Division of Pediatric Infectious Diseases, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon; Department of Biochemistry, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.; Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; Division of Pediatric Infectious Diseases, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon. Electronic address: [email protected].

DOI: 10.1016/j.clim.2020.108573

Link outs

Subscription / membership required

Full Text Sources:

MeSH Terms: 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