Turton James P G, Reynaud Rachel, Mehta Ameeta, Torpiano John, Saveanu Alexandru, Woods Kathryn S, Tiulpakov Anatoly, Zdravkovic Vera, Hamilton Jill, Attard-Montalto Simon, Parascandalo Ray, Vella Cecil, Clayton Peter E, Shalet Stephen, Barton John, Brue Thierry, Dattani Mehul T
Biochemistry, Endocrinology, and Metabolism Unit and London Centre for Paediatric Endocrinology, Institute of Child Health, London, United Kingdom.
J Clin Endocrinol Metab. 2005 Aug;90(8):4762-70. doi: 10.1210/jc.2005-0570. Epub 2005 May 31.
Mutations within the gene encoding the pituitary-specific transcription factor POU1F1 are associated with combined pituitary hormone deficiency (CPHD). Most of the affected individuals manifest GH, prolactin, and TSH deficiency.
We have now screened 129 individuals with CPHD and isolated GH deficiency for mutations within POU1F1.
Causative mutations were identified in 10 of 129 individuals (7.8%). Of these, five patients harbored the dominant negative R271W mutation, which is a well-recognized mutational hot spot. We have also identified a second frequently occurring mutation, E230K, which appears to be common in Maltese patients. Additionally, we describe two novel mutations within POU1F1, an insertion of a single base pair (ins778A) and a missense mutation (R172Q). Functional studies have revealed that POU1F1 (E230K) is associated with a reduction in transactivation, although DNA-binding affinity is similar to the wild-type protein. On the other hand, POU1F1 (R172Q) is associated with a reduction in DNA binding and transactivation, whereas POU1F1 (ins778A) is associated with loss of DNA binding and a reduction in transactivation.
Our data suggest that the phenotype associated with POU1F1 mutations may be more variable, with the occasional preservation of TSH secretion. Additionally, our data revealed POU1F1 mutations in three patients who were diagnosed as having ACTH deficiency but who, on further evaluation, were found to have normal cortisol secretion. Hence, elucidation of the genotype led to further evaluation of the phenotype, with the cessation of cortisol replacement that had been commenced unnecessarily. These data reflect the importance of mutational analysis in patients with CPHD.
编码垂体特异性转录因子POU1F1的基因内的突变与联合垂体激素缺乏症（CPHD）相关。大多数受影响个体表现出生长激素、催乳素和促甲状腺激素缺乏。
我们现在对129例CPHD和孤立性生长激素缺乏症患者进行了POU1F1基因内突变的筛查。
在129例个体中有10例（7.8%）鉴定出致病突变。其中，5例患者携带显性负性R271W突变，这是一个公认的突变热点。我们还鉴定出了第二个常见突变E230K，该突变在马耳他患者中似乎很常见。此外，我们描述了POU1F1基因内的两个新突变，一个单碱基对插入（ins778A）和一个错义突变（R172Q）。功能研究表明，POU1F1（E230K）与反式激活减少有关，尽管其DNA结合亲和力与野生型蛋白相似。另一方面，POU1F1（R172Q）与DNA结合和反式激活减少有关，而POU1F1（ins778A）与DNA结合丧失和反式激活减少有关。
我们的数据表明，与POU1F1突变相关的表型可能更具变异性，偶尔会保留促甲状腺激素分泌。此外，我们的数据显示，3例被诊断为促肾上腺皮质激素缺乏但进一步评估发现皮质醇分泌正常的患者存在POU1F1突变。因此，基因型的阐明导致了对表型的进一步评估，停止了不必要开始的皮质醇替代治疗。这些数据反映了CPHD患者突变分析的重要性。
