Research Projects

Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immune deficiency disease (PID) classified under combined immunodeficiency disorder by the International Union of Immunological Societies (IUIS) in 2022. WASP is a cytosolic protein that has an established role in the effective functioning of actin cytoskeletal architecture in hematopoietic cells, with other crucial established roles in the migration of lymphoid and myeloid cells, phagocytosis receptor signaling, and cytotoxicity. It regulates cytoskeletal rearrangement through activation of the Arp2/3 complex. There are multiple immunological functions dependent on the normal actin cytoskeleton, including lymphoid cell proliferation, immune synapse assembly and signaling, lymphoid and myeloid cell migration, as well as natural killer cell cytolytic activity and phagocytosis. In the last decade at PGIMER, Chandigarh, India, a tertiary care referral institute and a Government of India recognized Center for Advanced Research (CAR) in Primary Immune Deficiency diseases and Bone Marrow Transplant, more than 70 children with WAS/XLT have been diagnosed and treated. We published our first clinical experience in a small series of 8 patients in 2012 (Suri D et al., 2012) and later collated data of 108 patients (60 from our centre) from various Indian centres to project novel genotypes and challenges in diagnosis and treatment in our country from India. Currently, we follow one of the largest cohorts of WAS/XLT patients and patients are referred from across the country. Offering HSCT the only curative therapy to patients with milder disease remains a clinical challenge in developing countries. Thus, profound phenotypic variability and poor predictors for autoimmunity and malignancy adds clinical and therapeutic challenges to management of this disease. A need is felt to study functional dynamics of WASP which will help in improving understanding the effect of mutations and have clinical implications to predict phenotypic variations in this disease better. The present study aims to understand the molecular and functional consequences of disruptions in the WASP-WIP axis in patients with WAS. Specifically, it seeks to elucidate how genetic variants affecting either WASP or WIP alter their interaction, impact actin cytoskeletal dynamics, and influence post-translational regulation through ubiquitination. Disruption of this interaction-either due to mutations in WASP or WIPF1 (WIP gene) has been shown to destabilize WASP and impair actin polymerization, leading to defective immune synapse formation, impaired T-cell activation, and abnormal migration of immune cells. Notably, WIP deficiency has been identified in a WAS-like immunodeficiency, further emphasizing the functional interdependence of WASP and WIP in immune homeostasis. While the structural and biochemical roles of WASP and WIP have been described, limited studies exist that correlate genetic variants with downstream functional consequences at the molecular level. In particular, the impact of variant-specific WASP-WIP disruption on actin polymerization dynamics and WASP ubiquitination in human primary cells remains underexplored. We planned a prospective single centre observational study with a convenient sample size of 15 patients with mutation in WASP gene. Deploying computational and experimental approaches simultaneously we wish to evaluate WAS-WIP axis and correlate the effect of genetic variants on WAS/WIP protein interaction and function. Further, we would like to compare actin cytoskeleton dynamics in patients with disrupted or intact WAS-WIP axis. Additionally, we would also study the ubiquitination of WASP in these patients.