Prevalence of GH-1 gene deletion in patients with isolated growth hormone deficiency in Japan

A multicenter study was carried out to investigate the prevalence of growth hormone (GH-1) gene deletions among patients with isolated growth hormone deficiency (IGHD) and extremely short stature in Japan, using PCR method. G enomic DNA was extracted from the whole blood samples of 48 patients (34 ma les and 14 females) at 20 hospitals. All the patients fulfilled the inclusi on criteria as follows: (1) IGHD patients whose every peak serum GH level i n more than two tests < 5 ng/ml and (2) pretreatment height < -3SD, regardl ess of family history and facial feature characteristic of GH-I gene deleti on. The subjects were screened for deletions in GH-1 gene, using a PCR meth od that could identify deletions of 6.7, 7.0 and 7.6 kbp. Three (6.25%) out of 48 subjects were found to have such deletion fragments. The first case was a boy homozygous for deletion of 6.7 kbp fragments. The second case was a girl heterozygous for 6.7 kbp deletion. A direct sequence analysis revea led a 2-bp deletion in exon 3 on the remaining allele that created a stop c odon in exon 4. The third case was a boy also heterozygous for 6.7 kbp dele tion. By direct sequencing analysis, three point mutations were detected in the promoter region on the opposite allele together with a four-base addit ion at base 250. One of the mutations was in the area of Pit-1 binding site (at base - 123). The latter two cases apparently represent new types of co mpound heterozygote of GH-1 gene deletion. Our results suggest that GH-1 ge ne mutation is not so rare in extremely short IGHD children in Japan.