An exonic mutation of the GH-1 gene causing familial isolated growth hormone deficiency type II.

A heterozygous base change was identified in exon 3 of the growth hormone (GH)-1 gene in a Japanese family with autosomal dominant GH deficiency. All of the patients from this family had a heterozygous G to T transversion at the first 5'-site nucleotide of exon 3. Analysis of the GH-1 cDNA, synthesized from lymphoblasts of the patients, revealed an abnormal shorter transcript as well as a normal-sized transcript. Direct sequencing of this abnormal transcript showed that the transcript completely lacked exon 3. In familial isolated GH deficiency (IGHD) type II, several heterozygous mutations have been reported at the donor splice site in intron 3 of the GH-1 gene or inside intron 3, which causes aberrant GH messenger RNA splicing, resulting in the deletion of exon 3. This deletion causes a lack of amino acid residues 32-71 in the mature GH protein. This mutant GH is well-known to exert a dominant negative effect on the secretion of mature normal GH protein. Thus, in the subject family, a heterozygous G-to-T transversion at the first nucleotide of the exon 3 deletes exon 3 in mature GH mRNA and causes GH deficiency. The present authors suggest that the first nucleotide of exon 3 is critical for the splicing of GH-1 mRNA.