Laboratory of Human Genetics, Department of Medical Sciences, Eastern Piedmont University and Interdisciplinary Research Center on Autoimmune Diseases, 28100 Novara, Italy.
J Endocrinol Invest. 2009 Sep;32(8):653-8. doi: 10.1007/BF03345736. Epub 2009 May 12.
Mutations in the gene encoding the pituitary transcription factor POU1F1 (Pit-1, pituitary transcription factor-1) have been described in combined pituitary hormone deficiency (CPHD).
The aim of this study was the characterisation of the molecular defect causing CPHD in a patient born to consanguineous parents.
The case of a 12.5-yr-old girl presenting with severe growth failure at diagnosis (-3 SD score at 3 months) and deficiency of GH, PRL, and TSH was investigated for the presence of POU1F1 gene mutations by denaturing high performance liquid chromatography analysis.
A novel mutation adjacent to the IVS2 splicing acceptor site (IVS2-3insA) was identified in the patient at the homozygous state. Analysis of patient's lymphocyte mRNA and an in vitro splicing assay revealed the presence of 2 aberrant splicing products: a) deletion of the first 71 nucleotides of exon 3, altering the open reading frame and generating a premature stop codon, b) total exon 3 skipping resulting in an in frame deleted mRNA encoding a putative protein lacking part of the transactivation domain and of the POUspecific homeodomain. Notably, the patient's relatives heterozygous for the mutation had PRL levels under the normal range with no evident clinical symptoms.
The IVS2- 3insAmutation, responsible for CPHD at the homozygous state, causes the presence of 2 aberrant splicing products encoding non-functional products. In the heterozygotes one normal allele might not guarantee a complete pituitary function.
编码垂体转录因子 POU1F1（Pit-1，垂体转录因子-1）的基因突变已在联合垂体激素缺乏症（CPHD）中描述。
本研究的目的是描述在一对近亲父母所生的患有 CPHD 的患者中导致 CPHD 的分子缺陷。
对一名 12.5 岁女孩进行了研究，该女孩在诊断时（3 个月时的-3SD 评分）存在严重的生长发育迟缓，且缺乏 GH、PRL 和 TSH，通过变性高效液相色谱分析检测 POU1F1 基因突变。
在患者的纯合状态下发现了一个紧邻 IVS2 剪接受体位点的新突变（IVS2-3insA）。对患者淋巴细胞 mRNA 的分析和体外剪接试验表明存在 2 种异常剪接产物：a）缺失外显子 3 的前 71 个核苷酸，改变开放阅读框并产生过早终止密码子，b）外显子 3 完全跳过，导致编码推定蛋白的无义 mRNA，该蛋白缺乏部分反式激活域和 POUspecific 同源结构域。值得注意的是，突变的杂合亲属的 PRL 水平处于正常范围，没有明显的临床症状。
导致纯合状态下 CPHD 的 IVS2-3insA 突变导致存在 2 种异常剪接产物，编码无功能产物。在杂合子中，一个正常的等位基因可能不能保证完全的垂体功能。
