A growth hormone receptor mutation impairs growth hormone autofeedback signaling in pituitary tumors.
Pituitary tumors are a diverse group of neoplasms that are classified based on clinical manifestations, hormone excess, and histomorphologic features. Those that cause growth hormone (GH) excess and acromegaly are subdivided into morphologic variants that have not yet been shown to have pathogenetic significance or predictive value for therapy and outcome. Here, we identify a selective somatic histidine-to-leucine substitution in codon 49 of the extracellular domain of the GH receptor (GHR) in a morphologic subtype of human GH-producing pituitary tumors that is characterized by the presence of cytoskeletal aggresomes. This GHR mutation significantly impairs glycosylation-mediated receptor processing, maturation, ligand binding, and signaling. Pharmacologic GH antagonism recapitulates the morphologic phenotype of pituitary tumors from which this mutation was identified, inducing the formation of cytoskeletal keratin aggresomes. This novel GHR mutation provides evidence for impaired hormone autofeedback in the pathogenesis of these pituitary tumors. It explains the lack of responsiveness to somatostatin analogue therapy of this tumor type, in contrast to the exquisite sensitivity of tumors that lack aggresomes, and has therapeutic implications for the safety of GH antagonism as a therapeutic modality in acromegaly.
Asa
Sylvia L
SL
Department of Pathology, University Health Network and Toronto Medical Laboratories, Mount Sinai Hospital, Ontario Cancer Institute, Toronto, Ontario, Canada. sylvia.asa@uhn.on.ca
Digiovanni
Rebecca
R
Jiang
Jing
J
Ward
Megan L
ML
Loesch
Kimberly
K
Yamada
Shozo
S
Sano
Toshiaki
T
Yoshimoto
Katsuhiko
K
Frank
Stuart J
SJ
Ezzat
Shereen
S
D000236:Adenoma / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D025461:Feedback, Physiological / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction
D002352:Carrier Proteins; D010446:Peptide Fragments; C051815:somatotropin-binding protein