Hendriks-Stegeman B I, Augustijn K D, Bakker B, Holthuizen P, van der Vliet P C, Jansen M
Department of Pediatric Endocrinology, University Medical Center, 3508 AB Utrecht, The Netherlands.
J Clin Endocrinol Metab. 2001 Apr;86(4):1545-50. doi: 10.1210/jcem.86.4.7371.
The POU homeodomain containing transcriptional activator POU1F1, formerly called Pit1 or GHF-1, is required for the embryological determination and postnatal secretory function of the GH-, PRL-, and TSH-producing cells in the anterior pituitary. Several mutations in the gene encoding POU1F1 have been described, resulting in a syndrome of combined pituitary hormone deficiency involving these three hormones. Most of the patients with this phenotype have either a dominant negative mutation in codon 271 (R271W) or are homozygous for a recessive mutation in the POU1F1 gene; to date only one case has been reported with compound heterozygosity for two point mutations. Here, we describe a boy with severe deficiencies of GH, PRL, and TSH who had compound heterozygosity for two novel point mutations in the POU1F1 gene: a 1-bp deletion frameshift mutation (747delA), the first one described to date in this gene, which leads to a nonfunctional truncated protein lacking the entire DNA recognition helix of the POU homeodomain, and a missense mutation in the C-terminal end of the fourth alpha-helix of the POU-specific domain (W193R),which causes a 500-fold reduction in the ability to bind to DNA and activate transcription.
含POU同源结构域的转录激活因子POU1F1，以前称为Pit1或GHF-1，对于垂体前叶产生生长激素（GH）、催乳素（PRL）和促甲状腺激素（TSH）的细胞的胚胎期分化及出生后分泌功能是必需的。已描述了编码POU1F1的基因中的几种突变，导致涉及这三种激素的联合垂体激素缺乏综合征。大多数具有这种表型的患者在密码子271处有显性负性突变（R271W），或者是POU1F1基因隐性突变的纯合子；迄今为止，仅报道了1例具有两个点突变的复合杂合性病例。在此，我们描述了一名患有严重GH、PRL和TSH缺乏症的男孩，他在POU1F1基因中有两个新的点突变的复合杂合性：一个1bp缺失移码突变（747delA），这是该基因中迄今为止描述的第一个此类突变，导致产生一种无功能的截短蛋白，该蛋白缺乏POU同源结构域的整个DNA识别螺旋，以及一个位于POU特异性结构域第四α螺旋C末端的错义突变（W193R），该突变导致与DNA结合并激活转录的能力降低500倍。
