Zhang, Yu

Inborn errors of immunity (IEI) presenting with immunodeficiency and autoimmunity can illuminate pathways essential for immunocompetence and self-tolerance. We recently characterized a new IEI named MAGIS (“Midline malformations of the brain, Anterior pituitary gland dysfunction, Growth retardation, Immunodysregulation/Immunodeficiency, and Skeletal defects”) caused by heterozygous germline-activating mutations in GNAI2 (encoding the heterotrimeric G protein, Gαi2). This disorder demonstrates the central role of Gαi2 regulation of chemotaxis in humans and a novel pathway by which G proteins regulate T cell activation. Here, we review the clinical features, current genetic and biochemical understanding, and future therapeutic considerations for this new syndromic immune dysregulation disorder.

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2 , which encodes G αi2 , a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase–mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G αi2 mutations had clinical presentations that included impaired immunity. Mutant G αi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G αi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)–activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal–regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)–AKT S6 signaling to drive cellular growth and proliferation.