Activating mutations of STAT3: Impact on human growth

Abstract

The signal transducer and activator of transcription (STAT) 3 is the most ubiquitous member of the STAT family and fulfills fundamental functions in immune and non-immune cells. Mutations in the STAT3 gene lead to different human diseases. Germline STAT3 activating or gain-of-function (GOF) mutations result in early-onset multiorgan autoimmunity, lymphoproliferation, recurrent infections and short stature. Since the first description of the disease, the clinical manifestations of STAT3 GOF mutations have expanded considerably. However, due to the complexity of immunological characteristics in patients carrying STAT3 GOF mutations, most of attention was focused on the immune alterations. This review summarizes current knowledge on STAT3 GOF mutations with special focus on the growth defects, since short stature is a predominant feature in this condition. Underlying mechanisms of STAT3 GOF disease are still poorly understood, and potential effects of STAT3 GOF mutations on the growth hormone signaling pathway are unclear. Functional studies of STAT3 GOF mutations and the broadening of clinical growth-related data in these patients are necessary to better delineate implications of STAT3 GOF mutations on growth.