Human genetic variation provides a direct connection between molecular function and disease. Our group is interested in understanding the genetic determinants of disease and utilizing this information to define the mechanisms underlying pathologic processes. We use a combination of patient derived samples, mouse and cellular models, and in vitro biochemical tools to dissect these pathways. Our major focus is on characterizing autoinflammatory diseases, or diseases of constitutive activation of the innate immune system, frequently caused by genetic mutations. In particular our recent discovery of VEXAS Syndrome (Vacuoles, E1, X-linked, Autoinflammatory, Somatic Syndrome) a severe inflammatory disease affecting hundreds of thousands of individuals, that is caused by somatic mutations in UBA1, highlights the power of integrating clinical studies, human genetics, and molecular biology to uncover previously unrecognized pathways and diseases.
Identification of genetic causes of diseases
Our group is interested in identifying the genetic causes of autoinflammatory disease using novel sequencing approaches and bioinformatic pipelines. We perform genetic sequencing of patient samples both from our integrated Center for Autoimmune and Autoinflammatory Genetic Diseases at NYU and from patients referred to us from other centers. This data is analyzed using multiple different genotype-first (Beck DB et al. NEJM 2021), and phenotype-based approaches (Beck DB, Basar MA et al. Science Advances 2021, Beck DB et al. AJHG 2020 b) with the goal of identifying new disease-causing genetic variants. These variants are then modeled in the laboratory to determine how they alter cellular pathways and how these alterations lead to key features of disease. This work has led to the identification of acquired genetic errors of immunity: immune dysregulation caused by cell-type restricted somatic mutations. We are analyzing exome and genome data from patients with suspected acquired errors of immunity and are identifying new variants in UBA1, and other genes, that will lead to additional diagnoses and mechanistic discoveries. Although focused on inflammatory diseases, our work has extended into other areas including developmental diseases, primary immunodeficiencies, and other undiagnosed cases. Our overall goal is to provide genetic diagnoses to facilitate treatment and management in patients and achieve the goal of molecular medicine.
Mechanistic insights into inflammation
Identifying the genetic causes of disease not only helps provide patients with a diagnosis, but uncovers pathways and regulatory processes that result in inflammation. We characterize these disease-causing variants in vitro, in patient samples, and in model organisms and correlate these findings with clinical manifestations in patients (Beck DB et al. NEJM 2021, Poulter JA et al. Blood 2021). Through these efforts we have discovered novel regulatory pathways critical for immune activation. Our recent efforts have focused on understanding the role of global ubiquitylation in fine tuning inflammation and cell death within immune cell subsets along with the role of specific ubiquitin chain types in cytokine production. Further characterization of such pathways, in mouse models of disease, will reveal new principles of regulation of human inflammation, which will translate to novel, more specific and effective therapeutic approaches.
Using human genetics to inform basic biology
Beyond using the identification of genetic variants for patient diagnosis and care, we also use information from human genetics to understand normal physiology and cell biology. These insights are derived from studying disease-causing genes and variants, and expanding to normal tissue. Through this work, we have uncovered important aspects of ubiquitylation during development (Beck DB et al Science Advances 2021), protein translation initiation, and vesicle formation. Specifically, we are interested in understanding the role of the ubiquitylation enzymes implicated in disease, under physiologic contexts. Our goal is to expand beyond the rare disease insights, and use human genetics and genomics to provide important insights in all individuals.