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A Novel Dysfunctional Growth Hormone Variant (Ile179Met) Exhibits a Decreased Ability to Activate the Extracellular Signal-Regulated Kinase Pathway

Section of Endocrinology (M.D.L., T.E.E., M.F.S.), Department of Medicine, Institute of Medical Genetics (M.H., D.S.M., V.N., A.M.P., D.N.C.), Department of Child Health (J.W.G.), University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, United Kingdom; Pharmacia AB (L.F.), Lindhagensgatan 98, SE-112 87, Stockholm, Sweden; Biovitrum AB (M.N.), Nordenflychtsvagen 62:6, SE-112 87, Stockholm, Sweden; Paediatric Endocrinology Unit (C.-J.D.V.), Hospital Virgen del Rocío, and Paediatric Endocrinology Unit (L.F.L.-C.), Hospital Militar Universitario, 41013 Sevilla, Spain; Paediatric Endocrinology Unit (J.P.L.-S.), Hospital Materno-Infantil Carlos Haya, 29011 Málaga, Spain; Paediatric Endocrinology Unit (R.C.), Hospital Reina Sofía, 14004 Córdoba, Spain; Paediatric Endocrinology Unit (N.D.-T.), Hospital Infanta Elena, 21007 Huelva, Spain; Paediatric Endocrinology Unit (R.E.), Hospital Universitario de Valme, 41014 Sevilla, Spain; and Medical Department (A.U.), Pharmacia Spain, Barcelona, Spain

Address all correspondence and requests for reprints to: Dr. Mark Lewis, Section of Endocrinology, Department of Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom. E-mail: lewismd{at}cardiff.ac.uk.

The pituitary-expressed GH1 gene was screened for mutation in a group of 74 children with familial short stature. Two novel mutations were identified: an Ile179Met substitution and a -360AG promoter variant. The Ile179Met variant was shown to exhibit a similar degree of resistance to proteolysis as wild-type GH, indicating that the introduction of Met does not cause significant misfolding. Secretion of Ile179Met GH from rat pituitary cells was also similar to that of wild type. Although receptor binding studies failed to show any difference in binding characteristics, molecular modeling studies suggested that the Ile179Met substitution might nevertheless perturb interactions between GH and the GH receptor loop containing the hotspot residue Trp169, thereby affecting signal transduction. The ability of the Ile179Met variant to activate a signal transducer and activator of transcription (STAT) 5-responsive luciferase reporter gene and induce phosphorylation of STAT 5 and ERK was therefore studied. In contrast to its ability to activate STAT 5 normally, activation of ERK by the Ile179Met variant was reduced to half that observed with wild type. Although differential effects on the activation of distinct signaling pathways by a mutant receptor agonist are unprecedented, these findings also suggest that the ERK pathway could play a role in mediating the action of GH.

This work was supported in part by Pharmacia AB, Stockholm, Sweden.

Abbreviations: GHR, GH receptor; JAK, Janus tyrosine kinase; SDS, SD score; STAT, signal transducer and activator of transcription.

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