GH-1 gene splicing mutations: molecular basis of hereditary isolated growth hormone deficiency in children.

Children, residents of the Russian Federation, with congenital isolated growth hormone deficiency, were screened for mutations of GH-1 gene, the main gene of this deficiency. Twenty-eight children from 26 families with total congenital isolated growth hormone deficiency were examined. Direct sequencing of GH-1 detected five splicing mutations in intron 2, intron 3, and exon 4, two of them were never described previously. Three dominant negative mutations of GH-1 splicing, the basis for autosomal dominant isolated growth hormone deficiency (type II), are presented: IVS2 -2A>T, IVS3 +2T>C, and IVS3 +1G<A. GH-1 is the main gene of type II isolated growth hormone deficiency in patients living in the Russian Federation. All detected mutations of GH-1 impair splicing processes, which distinguishes them from mutations in other forms of isolated growth hormone deficiency. The detected variety of GH-1 splicing mutations attests to allele genetic heterogeneity of this pathology. The "hot spot" of mutations is 5'-donor splicing site of GH-1 intron 3, while IVS3 +IG>A mutation can be regarded as the most incident in type II isolated growth hormone deficiency in the Russian population.