GH-IGF-I PathwayOur laboratory has a long-standing interest in growth failure resulting from molecular defects along the classical growth hormone (GH)-insulin-like growth factor (IGF)-I growth axis. Mutation discovery and critical assessment of causality through functional and cellular studies of identified variants, have provided valuable insights.

We identified the first inactivating STAT5B (Signal Transducer and Activator of Transcription 5B) mutations in patients who resembled patients carrying GHR (growth hormone receptor) defects, with severe postnatal growth failure, GH insensitivity (GHI) and severe IGF deficiency (IGFD).  A progressive auto-immune deficiency and often fatal pulmonary insufficiency is associated with STAT5B deficiency (OMIM #245590), a condition not recapitulated in Stat5b-/- knock-out mouse models. More recently, we described the first dominant-negative loss-of-function STAT5B defects which affected growth but left the immune system only mildly disturbed (Nat Commun, 2018). Current studies include delineating growth functions from immune functions of STAT5B, how perturbation of STAT5B lead to growth impairment, why the very closely related STAT5A cannot compensate for loss of STAT5B functions in humans (in contrast to mouse models). Patient-based iPSC (induced pluripotent stem cell) derived models (CuSTOM) complement standard in vitro reconstitution and cellular studies to improve our understanding the critical roles of STAT5B in human growth and immunity/pulmonary functions.

Grant Funding: 
National Institute of Health: R01 HD078592 Hwa (PI) 7/1/14 – 6/30/19
Roles of STAT5b in IGF-I production and human growth

 

 

STAT5B deficiency