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A Novel Mutation Affecting the Interdomain Link Region of the Growth Hormone Receptor in a Vietnamese Girl, and Response to Long-Term Treatment with Recombinant Human Insulin-Like Growth Factor-I and Luteinizing Hormone-Releasing Hormone Analogue¹

School of Paediatrics (J.L.W., L.M.N.), University of New South Wales, Randwick, New South Wales, 2031; John Hunter Children’s Hospital (P.A.C.), Newcastle, New South Wales, 2310; Department of Physiology and Pharmacology and Centre for Molecular Biology (S.N.B., S.W.R, M.J.W.), University of Queensland, St. Lucia, Queensland, 4072; Department of Paediatrics (T.J.C.B.), Nepean Hospital, Penrith, New South Wales, 2751 Australia

Address all correspondence and requests for reprints to: Jan L. Walker, Department of Endocrinology, Sydney Children’s Hospital, High Street, Randwick New South Wales, Australia 2031. E-mail: jan.walker{at}unsw.edu.au

A Vietnamese girl with Laron syndrome has been treated with recombinant human insulin-like growth factor-I for 4 yr from age 11.28 yr. Her height SD score increased from -6.3 to -4.7 without acceleration of bone age. Isolated breast development progressed despite pubertal suppression with luteinizing hormone-releasing hormone analogue, which was stopped after 3 yr because of growth deceleration. Facial coarsening was documented with serial photographs.

Sequencing and in vitro analysis identified a homozygous base pair substitution in exon 6 of the proband’s GH receptor (GHR), which changed amino acid 131 from proline to glutamine (P131Q) and disrupted GH binding. Both the P131Q-mutated human GHR and wild-type (wt) hGHR were transiently expressed in COS-1 cells, as demonstrated by Western blotting, but the P131Q-transfected cells did not bind ¹²⁵I-hGH. Similarly, FDC-P1 cells transfected with wthGHR bound ¹²⁵I-hGH with high affinity and proliferated in response to GH, whereas the P131Q hGHR cells did neither. In CHO-K1 cells cotransfected with wthGHR and the Egr-1 promotor linked to a luciferase reporter gene, GH evoked a 2.14 ± 0.21-fold increase in luciferase activity, but there was no response in the cells carrying the P131Q hGHR mutation. From examination of the crystal structure of the GHR, we suggest that the P131Q mutation disrupts the interdomain link between the extracellular domains of the GHR, causing a conformational change that results in disruption of the GH binding site.

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