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Publications of the Week

Human Complete NFAT1 Deficiency Causes a Triad of Joint Contractures, Osteochondromas, and B Cell Malignancy

By July 25, 2022No Comments

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This week we profile a recent publication in Blood from Dr. Mehul Sharma (pictured, left) and a team from the lab of Dr. Stuart Turvey (right) at UBC.

Can you provide a brief overview of your lab’s current research focus?

One part of our lab focuses on research in inborn errors of immunity (IEIs). IEIs are monogenic disorders that result in an increased susceptibility to infectious disease, autoinflammatory disease, allergy, or autoimmunity. We start with a population of children with a defined infectious or inflammatory disease phenotype and then aim to understand the underlying cellular, molecular and genetic abnormalities responsible for the disease through detailed immunological, genomic and proteomic analysis. Through this process we generate knowledge that will aid in the diagnosis and management of the patients, elucidate mechanisms of disease pathogenesis and, ultimately, identify novel targets for anti-inflammatory and anti-infectious therapeutic agents.

What is the significance of the findings in this publication?

In this publication we describe the first human with complete NFAT1 deficiency. Based on our study, patients should be worked up for possible NFAT1 deficiency if they present with the following triad of features: progressive joint contractures, osteochondromas, B cell malignancy. Identification of future patients with NFAT1 deficiency will lead to better clinical management and guidance for these patients and their families. Furthermore, this study highlights the pleiotropic role of NFAT1 in human immunity. Finally, since NFAT1 is inhibited by calcineurin inhibitors, which are needed for preventing organ rejection and graft-versus-host disease in transplant recipients, our publication on human NFAT1 deficiency defines the important/detrimental effects associated with long-term use of calcineurin inhibitors.

What are the next steps for this research?

Going forward we would like to further understand the role of NFAT1 in human biology. It will be important to further study T cell activation and exhaustion, as well B cell hyperactivation, in the context of NFAT1 deficiency. Together these steps might elucidate the exact mechanism driving recurrent B cell lymphoma in this patient. This will help identify potential therapeutic strategies for B cell lymphoma treatment in this patient that might differ from conventional lymphoma therapies. This research will also shed light onto the role of calcium signaling in different types of B cell lymphomas. Finally, NFAT1 has been associated with type-2 diabetes in genome wide association studies. Future steps will test the hypothesis that our patient is predisposed to type 2 diabetes and explore any linked mechanism with NFAT1 deficiency.

If you’d like to mention your funding sources, please list them.

This work was supported by grants from Genome BC, the Canadian Institutes of Health Research, and the BC Children’s Hospital and foundation for their support of the Rare Disease Discovery Hub.

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