PhD Student, Postgraduate Institute of Medical Education and Research
Multi-omic study of defective WASp protein and its interaction with ATP-Dependent CRC Complex
Wiskott Aldrich syndrome (WAS) is an X-linked disorder characterized by a clinical triad of thrombocytopenia, eczema and immunodeficiency. This kind of primary immunodeficiency disorder (PID) has a wide spectrum of clinical manifestations with varied phenotypes. It encompasses children with X-linked thrombocytopenia (XLT), who manifest only with mild or intermittent thrombocytopenia and also children with classic WAS who have severe disease along with autoimmune manifestations and malignancy. Molecular mechanism involved in the disease is attributed to mutations in the WAS gene. X-linked neutropenia is a rare condition also caused by gain of function mutation in the WAS gene. WAS gene encodes for WASp protein which is expressed in all the hematopoietic cells and is involved in various cellular pathways.
According to International Union of Immunological Societies (IUIS), there are at least 300 monogenic disorders of immunity. Long back, these were considered as rare diseases, however recent data suggest that they are not uncommon, but were probably under recognized and under diagnosed. With the availability of better diagnostic tests the prevalence of these disorders are thought to be 1 in 10,000 population Functioning of WASp was classically considered to be restricted within the cytoplasm, but in recent years, its nuclear role is being increasingly recognized. Immune system has two arms, humoral i.e. immunity provided through humors (cell-free fluid or serum) mediated by B cells and cell-mediated immunity which is provided by different cells of myeloid lineage (monocytes, macrophages, neutrophils, basophils, eosinophils, platelets, dendritic cells and erythrocytes) and lymphoid lineage (T cells, and natural killer cells). The PIDs can have defects in one arm or both. WAS is classified under combined immunodeficiencies (CID) with associated and syndromic features by IUIS.
We therefore wish to study CRC complex in T cell, B cells and monocytes. Then, to evaluate if this could help in molecular characterization of the mutation. The information thus generated may aid to differentiate XLT from classic WAS and assess the severity of the mutations.
At the end of the study, genotype-phenotype correlation along with the epigenetic effects of the WASp will be established. This will help in understanding the underlying defects leading to immunodeficiency and autoimmune manifestations of the disease.
Abstract: Patients with Wiskott-Aldrich syndrome (WAS) are predisposed to malignancy and autoimmunity in addition to infections. We report a male child with WAS, who had presented with recurrent pneumonia, eczema, thrombocytopenia, autoimmune hemolytic anemia, and vasculitic skin lesions. Genetic analysis revealed a classical genotype WAS 155C>T; R41X. At 2 years of follow-up, he developed persistent headache and progressive hepatomegaly. Brain imaging showed a mass in the right frontal region, which on histopathology was shown to be high-grade non-Hodgkin lymphoma. Magnetic resonance cholangiopancreatography showed features of sclerosing cholangitis. This report extends the clinical spectrum and highlights unusual manifestations of sclerosing cholangitis and intracranial lymphoma in a patient with WAS.
Pub.: 28 Aug '16, Pinned: 21 Sep '17
Abstract: The Wiskott-Aldrich syndrome (WAS) is a rare genetic disease characterized by thrombocytopenia, immunodeficiency, autoimmunity, and hematologic malignancies. Secondary mutations leading to re-expression of WAS protein (WASP) are relatively frequent in patients with WAS.The tissue distribution and function of revertant cells were investigated in a novel case of WAS gene secondary mutation.A vast combination of approaches was used to characterize the second-site mutation, to investigate revertant cell function, and to track their distribution over a 18-year clinical follow-up.The WAS gene secondary mutation was a 4-nucleotide insertion, 4 nucleotides downstream of the original deletion. This somatic mutation allowed the T-cell-restricted expression of a stable, full-length WASP with a 3-amino acid change compared with the wild-type protein. WASP(+) T cells appeared early in the spleen (age 10 years) and were highly enriched in a mesenteric lymph node at a later time (age 23 years). Revertant T cells had a diversified T-cell-receptor repertoire and displayed in vitro and in vivo selective advantage. They proliferated and produced cytokines normally on T-cell-receptor stimulation. Consistently, the revertant WASP correctly localized to the immunologic synapse and to the leading edge of migrating T cells.Despite the high proportion of functional revertant T cells, the patient still has severe infections and autoimmune disorders, suggesting that re-expression of WASP in T cells is not sufficient to normalize immune functions fully in patients with WAS.
Pub.: 18 Feb '10, Pinned: 21 Sep '17