Kamijo T, Hayashi Y, Shimatsu A, Kinoshita E, Yoshimoto M, Ogawa M, Seo H
Department of Paediatrics, Nagoya University School of Medicine, Nagoya; Kamiida Daiichi General Hospital, Nagoya, Japan.
Clin Endocrinol (Oxf). 1999 Sep;51(3):355-60. doi: 10.1046/j.1365-2265.1999.00798.x.
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.
Five individuals diagnosed as IGHD: two sporadic cases and one family with three affected individuals (two siblings and their father).
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.
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.
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.
II型孤立性生长激素缺乏症（IGHD）是以常染色体显性方式遗传的一种疾病。在五个家族中已鉴定出GH - I基因第3内含子供体剪接位点的三个突变。在本报告中，我们描述了II型IGHD患者中同样位于第3内含子供体剪接位点的一种新突变。
五名被诊断为IGHD的个体：两例散发病例和一个有三名患者的家族（两名兄弟姐妹及其父亲）。
从外周血单个核细胞中提取基因组DNA。通过聚合酶链反应（PCR）扩增GH - I基因的所有外显子和内含子，并进行序列分析。
在家族性病例中发现第3内含子第5个碱基处发生了鸟嘌呤到腺嘌呤的转换（mutE），此前未见报道，而在包括祖父母在内的家族未患病成员中未发现。在另外两个散发病例家族中，在患病个体中发现第3内含子第1个碱基处发生了鸟嘌呤到腺嘌呤的转换（mutA），而在家族其他成员中未发现。
MutE此前未见报道，是与II型IGHD相关的第四个突变。mutA中发生突变的鸟嘌呤残基是CpG二核苷酸的第二个核苷酸，通过甲基化 - 脱氨基机制，该位点被认为是突变热点。由于此前在属于不同种族背景的三个II型IGHD家族中已鉴定出mutA，这似乎是IGHD显性遗传中最常见的GH - I基因突变。因为在本研究分析的所有三个家族中似乎都发生了新发突变，并且这些突变的有无可通过PCR和限制性内切酶消化轻松检测，所以不仅家族性病例，而且IGHD散发病例也应检测GH - 1基因第3内含子供体剪接位点是否可能存在突变。
