Mutations in intron 3 of GH-1 gene associated with isolated GH deficiency type II in three Japanese families

OBJECTIVE Isolated GH deficiency (IGHD) type II is a disorder inherited in an autosomal dominant manner. Three mutations at the donor splice site of intron 3 of the GH‐I gene have been identified in five families. In this report, we describe a novel mutation also at the donor splice site of intron 3 in patients with IGHD type II. PATIENTS Five individuals diagnosed as IGHD: two sporadic cases and one family with three affected individuals (two siblings and their father). MEASUREMENT Genomic DNA was extracted from peripheral mononuclear cells. All the exons and introns of the GH‐I gene were amplified by polymerase chain reaction (PCR) and subjected to sequence analysis. RESULTS A guanine to adenine transition at the fifth base of intron 3 (mutE), which has not been reported, was identified in the familial case but not in unaffected members of the family including the paternal grandparents. In the other two families with sporadic cases, a guanine to adenine transition at the first base of intron 3 (mutA) was identified in the affected subjects but not in other members of the families. CONCLUSION MutE has not been previously reported and is the fourth mutation associated with IGHD type II. The guanine residue mutated in mutA was the second nucleotide of a CpG dinucleotide, which is regarded as a hot spot for mutations by a methylation‐deamination mechanism. Since mutA has previously been identified in three type II IGHD kindreds belonging to different ethnic backgrounds, this appears to be the most frequent GH‐I gene mutation in IGHD with a dominant inheritance. Because de novo mutations appeared to have occurred in all three families analyzed in the present study and the presence or absence of these mutations can easily be tested by PCR and restriction enzyme digestion, not only the familial cases but also sporadic cases with IGHD should be examined for a possible mutation at the donor splice site of intron 3 in the GH‐1 gene.