Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation

• DOI: 10.1038/s41467-018-04521-0
• Publication Date: 2018-05-22T15:49:02Z
• Authors: Jürgen Klammt; David Neumann; Evelien F. Gevers; Shayne F. Andrew; I. David Schwartz; Denise Rockstroh; Roberto Colombo; Marco A. Sanchez; Doris Vokurkova; Julia Kowalczyk; Louise A. Metherell; Ron G. Rosenfeld; Roland Pfäffle; Mehul T. Dattani; Andrew Dauber; Vivian Hwa
• Keywords: Male; 0301 basic medicine; Adolescent; Human Growth Hormone; Science; Q; Eczema; Mutation, Missense; Infant; Immunoglobulin E; Response Elements; Article; Laron Syndrome; Cell Line; 3. Good health; 03 medical and health sciences; HEK293 Cells; STAT5 Transcription Factor; Humans; Female; Genetic Predisposition to Disease; Insulin-Like Growth Factor I; Child; Germ-Line Mutation

AbstractGrowth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently, postnatal growth impaired. Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications. Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. Importantly, each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B. We conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system.