Mutations in Intron 3 of GH-I Gene in Japanese Families with Isolated GH Deficiency Inherited in an Autosomal Dominant Manner.

Abstract

Three kinds of point mutations at the donor splice site of intron 3 of GH-I gene were identified in 8 Japanese patients (5 families) with isolated GH deficiency (IGHD). De novo cases were present in all families and IGHD was transmitted to the next generation in autosomal dominant manner (type II-IGHD). Since the presence or the absence of these mutations can be easily detected by PCR and restriction enzyme digestion, possible de novo mutations in GH-I should be screened in subjects with IGHD, even in sporadic cases. All the three mutations described herein affect splicing of GH-I gene, generating an mRNA lacking exon 3. The 17.5-kD GH protein translated from the mutant mRNA is not secreted from the cell. Moreover, the 17.5-kD GH inhibited the secretion of co-expressed wild-type 22-kD GH in neuroendocrine cells, indicating that the dominant negative effect of 17.5-kD GH is responsible for the pathogenesis of type II-IGHD.