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 analogue.
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Walker JL, Crock PA, Behncken SN, Rowlinson SW, Nicholson LM, Boulton TJ, Waters MJ
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 analogue.
J Clin Endocrinol Metab. 1998 Jul;83(7):2554-61.
- PubMed ID
- 9661642 [ View in PubMed]
- Abstract
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 wildtype (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.