title: A novel C-terminal growth hormone receptor (GHR) mutation results in impaired GHR-STAT5 but normal STAT-3 signaling.
abstract: GH insensitivity (GHI) is an autosomal recessive disorder caused by defects in the GH receptor (GHR). In a 17-yr-old female with severe short stature and biochemical features of GHI, sequencing of GHR gene revealed a compound heterozygosity for two novel mutations: C83X and a G deletion at position 1776 (1776del). 1776del is predicted to result in GHR truncation to 581 amino acids with a nonsense sequence of residues 560-581. To clarify the effect of 1776del on GHR function, wild-type GHR, GHR-1776del, and two additional GHR mutants, GHR-L561X (stop codon at site of the 1776del) and GHR-I582X (translation termination in GHR-1776del) were transiently expressed in CHO cells. After incubation with recombinant human GH, GHR-1776del showed lower signal transducer and activator of transcription 5 (STAT5)-mediated transcriptional activation ( approximately 50%, P < 0.05), as well as STAT5 Tyr694 phosphorylation (P < 0.05) compared with wild-type GHR, whereas GHR-L561X and GHR-I582X showed normal STAT5 phosphorylation and transcriptional activity. In contrast, all vectors produced similar effects on STAT3-mediated transcriptional activation. In conclusion, this novel GHR-1776del mutation in a classical GHI patient illustrates an important mechanism of impaired GHR-STAT5 but intact GHR-STAT3 signaling. This effect might result from interference of C-terminal nonsense sequence in mutated GHR with STAT5 docking to upstream tyrosine residues.
authors.affiliation: Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Building 10, Suite 9D42, Bethesda, Maryland 20892, USA. tiulpaka@mail.nih.gov
authors.forename: Anatoly
authors.initials: A
authors.lastname: Tiulpakov
authors.forename: Petr
authors.initials: P
authors.lastname: Rubtsov
authors.forename: Ivan
authors.initials: I
authors.lastname: Dedov
authors.forename: Valentina
authors.initials: V
authors.lastname: Peterkova
authors.forename: Olga
authors.initials: O
authors.lastname: Bezlepkina
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
authors.forename: Ze'ev
authors.initials: Z
authors.lastname: Hochberg
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D006801:Humans; D046150:Laron Syndrome / Q000235:genetics*; D008894:Milk Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011986:Receptors, Somatotropin / Q000737:chemistry / Q000235:genetics*; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D015533:Transcriptional Activation; D014443:Tyrosine / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011986:Receptors, Somatotropin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine