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 ANALOG

A Vietnamese girl with Laron syndrome has been treated with recombinan t human insulin-like growth factor-I for 4 yr from age 11.28 yr. Her h eight so score increased from -6.3 to -4.7 without acceleration of bon e age. Isolated breast development progressed despite pubertal suppres sion with luteinizing hormone-releasing hormone analogue, which was st opped 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 proban d's GH receptor (GHR), which changed amino acid 131 from proline to gl utamine (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 I-125-hGH. Similarly, FDC-P1 cells transfected with wthGH R bound 125I-hGH with high affinity and proliferated in response to GH , whereas the P131Q hGHR cells did neither. In CHO-K1 cells cotransfec ted 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 mutati on. From examination of the crystal structure of the GHR, we suggest t hat the P131Q mutation disrupts the interdomain link between the extra cellular domains of the GHR, causing a conformational change that resu lts in disruption of the GH binding site.