ALLELIC VARIATIONS IN THE HUMAN GROWTH HORMONE-1 GENE PROMOTER OF GROWTH HORMONE-DEFICIENT PATIENTS AND NORMAL CONTROLS

Objective: Isolated growth hormone deficiency (IGHD) type IB is sugges ted to be more probably due to alterations in the genes directly invol ved in the hypothalamo-pituitary axis and/or in the specific transcrip tional regulation (cis-trans coupling) of the hGH-1 gene than to alter ations in the gene itself. In this study we analyzed the hGH-1 gene pr omoter region for structural alterations and allelic variations. Metho ds: The hGH-1 gene promoter region was analyzed by PCR, cycle sequenci ng and direct-blotting electrophoresis in a total of 212 individuals i ncluding 113 patients with IGHD type IB, 21 unaffected family members and 78 normal controls. Results: Twenty-two sequence variation sites w ere identified, Of these, 14% were located around the region of -1075b p, 77% between -550bp and the translational start site (+1bp) and 9% w ithin the first intron. Only one variation site affected a characteriz ed cis-acting element, namely that of NF-1. Importantly, all the varia tions found in patients were also observed in non-affected family memb ers as well as in normal unrelated controls. Conclusions: These findin gs imply that it is not a single variation within the GH-1 gene promot er, and therefore in the cis-acting elements, which causes IGHD, Howev er, we can not exclude the possibility that combinations of variations might perturb expression. Furthermore, these data illustrate the norm al heterogeneity of the GH-1 gene promoter region, a fact that has to be borne in mind whenever transcriptional studies are performed.