A novel and de novo splice-donor site mutation in intron 3 of the GH-1 gene in a patient with isolated growth hormone deficiency.

Heterozygous mutations at the splice-donor site of inron 3 of the GH-1 gene are known to affect growth hormone (GH) mRNA splicing and cause isolated GH deficiency (IGHD), which is inherited in an autosomal dominant trait. We report here a novel and de novo heterozygous IVS3 + 6T --> G mutation of the GH-1 gene in a Japanese patient with IGHD. RT-PCR analyses of the GH-1 minigene transcripts demonstrated that the IVS3 + 6T --> G mutation causes complete skipping of exon 3. We found a heterozygous IVS4 + 18G --> T polymorphism of the GH-1 gene in the patient, which was shared by the father, but not by the mother. Sequencing of individual alleles of the patient's GH-1 gene confirmed that the IVS3 + 6T --> G mutation and the IVS4 + 18G --> T polymorphism exist on the same chromosome. These findings indicate that the IVS3 + 6T --> G mutation arose in a germ cell of the father and caused IGHD in the patient.