PREVALENCE OF HUMAN GH-1 GENE ALTERATIONS IN PATIENTS WITH ISOLATED GROWTH-HORMONE DEFICIENCY

Human GH is encoded by the GH-1 gene which belongs to the GH gene clus ter encompassing a distance of about 65 kb on the long arm of chromoso me 17. Familial isolated growth hormone deficiency (IGHD) is associate d with at least four Mendelian disorders. These include two forms that have autosomal recessive inheritance (IGHD types IA and 1B) as well a s autosomal dominant (IGHD type II) and X-linked (IGHD III) forms. The aim of our study was to evaluate the prevalence of all GH-1 gene alte rations by sequencing the whole GH-1 gene after PCR amplification amon g 151 affected subjects from 83 families with severe IGHD (height: <-4 .5 SD score). A high frequency of GH-1 gene alterations was found in f amilies with IGHD type IA (8/12, 66.7%), whereas only a low frequency of GH-1 gene defects was present in all the other GH-deficient familie s (7/71, 9.9%). The absolute frequency of GH-1 gene deletions was 8.7% (6/69), 11.8% (4/34), and 18.7% (9/48) in Northern Europeans, Mediter raneans, and Asians, respectively, giving an overall frequency of 12.5 % (19/151). The sizes of the deletions were heterogeneous with the mos t frequent (78%) being 6.7 kb. In addition, 6% (9/151) of the patients presented GH-1 gene mutations such as frameshift, stop codon and spli cing error. Furthermore, total GH-1 gene abnormalities varied among di fferent populations from 11.6% in Northern Europe, 14.7% in Mediterran ean countries and 31.2% in Asia. Most striking, however, was the low f requency rate of 1.7% (2/119) of GH-1 gene mutations responsible for t he most common phenotype of IGHD, namely type IB, among the subjects c haracterized by the production of deficient but detectable amounts of GH after provocative stimuli. This finding underlines the necessity to focus rather on the promoter region of the GH-1 gene (cis-acting elem ents and trans-acting factors), and on other candidate genes specific for the GH axis than the GH-1 gene itself to define genetically the IG HD type IB phenotype in more detail.