David Beck (United States of America)
New York York University Grossman School of Medicine
Center for Human Genetic and Genomics
David received his MD/PhD at New York University School of Medicine where he studied biochemistry and cell fate decisions in the laboratory of Dr. Danny Reinberg. He performed further clinical training at Columbia University in Internal Medicine and the National Institutes of Health in clinical genetics. David performed his postdoctoral research with Dr. Dan Kastner at the National Human Genome Research Institute studying the genetics and mechanism underlying a subset of rheumatic diseases called autoinflammatory syndromes. David’s work focused on discovering and characterizing new genetic diseases, including VEXAS syndrome which he will talk about today. David joined the faculty at New York University School of Medicine last year to run a translational program studying autoinflammatory diseases, including VEXAS syndrome, both in the clinic and in the laboratory. His independent work focuses on trying to identify genetic causes of diseases in patients, and use laboratory investigation to help provide insights for clinical care. He has won several awards including Burroughs Wellcome Fund Career Awards for Medical Scientists, K99/R00, and NIH Director’s award.

Presenter of 1 Presentation

 Congress Calendar

Auto-Inflammation and VEXAS

Date
05/04/2023
Room
Auditorium
Session Type
Plenary Session
Session Name
0180 - Plenary Session 01: Dysimmunity, Inflammation and MDS (ID 18)
Presenter
Lecture Time
09:15 - 09:30

Abstract

Abstract Body

Somatic UBA1 mutations have recently been recognized as the cause of an inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked autoinflammatory, somatic) syndrome. Patients with VEXAS syndrome are frequently diagnosed with myelodysplastic syndrome (MDS) and multiple myeloma and in addition have severe, systemic inflammation. UBA1 is the primary E1 enzyme required for initiating the majority of ubiquitylation in the cell, most disease-causing mutations occur at the start codon for the cytoplasmic isoform of the protein (p.Met41). These mutations lead to an isoform swap with loss of the normally active UBA1b (initiated from p.Met41) and emergence of a new catalytically impaired short isoform UBA1c specifically in mutated cells (initiated from p.Met67). Despite extensive investigation into the clinical manifestations of UBA1 mutations, very little is known about the mechanism of disease.

Here, we will outline the identification and molecular dissection of novel somatic mutations in UBA1 that lead to VEXAS syndrome. The majority of these mutations were identified through unbiased screening of exome sequencing data of patients with clinical manifestations similar to VEXAS syndrome but without a known pathogenic mutation. We systematically characterized these novel UBA1 mutations, and found that only p.Met41 mutations led to a loss of UBA1b levels and production of UBA1c, while all other variants did not alter isoform expression. Instead, these mutations reduce catalytic function of both cytoplasmic and nuclear isoforms through interfering with ATP binding, rendering the enzyme thermolabile, or specifically impairing the transfer of ubiquitin from UBA1 to the E2 enzyme. These results demonstrate that VEXAS disease causing mutations lead to a global loss of ubiquitylation through differing mechanisms. Finally, we will provide an update about the aberrant signaling leading to bone marrow failure and inflammation in VEXAS syndrome using patient cells, cell culture systems and animal models. This work will focus on single cell RNA sequencing studies in VEXAS syndrome and our preliminary data using mouse models of VEXAS syndrome. Together our work demonstrate the importance of proper levels of global ubiquitylation for bone marrow physiology.

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