Modeling of Hyperparathyroidism-Jaw Tumor Syndrome by Targeted Deletion of Hrpt2

甲状旁腺增生性颌骨肿瘤综合征（HPT-JT）是一种综合征，易使个体发生一种或多种良性或恶性甲状旁腺肿瘤、下颌骨和/或上颌骨骨化性纤维瘤、良性或恶性子宫肿瘤，以及较不常见的囊性肾病变、肾错构瘤或Wilm肿瘤。受影响的个体可能在其一生中发展多个原发性甲状旁腺，颌骨，子宫和/或肾脏肿瘤。编码parafibromin的HRPT 2肿瘤抑制基因（也称为CDC 73）的失活突变被确定为大多数受影响的激酶中HPT-JT的遗传原因。随后，散发性甲状旁腺癌，骨化性纤维瘤的下颌骨和肾肿瘤的屏幕显示两个生殖细胞和体细胞突变的HRPT 2。拟定的研究旨在解决在完整动物的病理生理学相关实验背景下，Hrpt 2/副纤维蛋白缺失促进甲状旁腺和颌骨肿瘤形成的机制。为了研究体外敲除Hrpt 2的病理生理学后果，已经产生了其中Hrpt 2基因侧接两个loxP位点的遗传工程小鼠，并将其与两种不同的转基因小鼠品系PTH-Cre和Wnt 1-Cre杂交。这些杂交将导致后代在甲状旁腺或下颌骨中分别具有Hrpt 2缺失。这两种小鼠模型的开发将为解剖HPT-JT、散发性甲状旁腺肿瘤和骨化性颌骨纤维瘤的分子基础提供一种手段，并最终能够开发新的诊断和治疗策略。

Hyperparathyroidism jaw-tumor syndrome (HPT-JT) is a syndrome that predisposes individuals to the development of one or more benign or malignant parathyroid tumors, ossifying fibromas of the mandible and/or maxilla, benign or malignant uterine tumors and, less commonly, cystic kidney lesions, renal hamartomas or Wilm's tumors. Affected individuals may develop multiple primary parathyroid, jaw, uterine and/or kidney tumors over the course of their lifetime. Inactivating mutations of theHRPT2 tumor suppressor gene (also called CDC73), encoding parafibromin, were identified as the genetic cause of HPT-JT in the majority of affected kindreds. Subsequently, screens of sporadic parathyroid carcinomas, ossifying fibromas of the mandible and renal tumors revealed both germline and somatic mutations of HRPT2. The proposed studies are designed to address the mechanisms through which loss of Hrpt2/parafibromin promotes neoplasia in the parathyroid glands and jaws, in the pathophysiologically relevant experimental context of an intact animal. To study the pathophysiological consequences of knockout of Hrpt2 in vitro, genetically- engineered mice in which the Hrpt2 gene is flanked by two loxP sites have been generated and will be crossed with two different transgenic mouse strains, PTH-Cre and Wnt1-Cre. These crosses will result in offspring with Hrpt2 deletion in the parathyroid glands or mandible, respectively. Development of these two mouse models will provide a means for dissecting the molecular basis of HPT-JT, sporadic parathyroid tumors and ossifying jaw fibromas and may ultimately enable the development of new diagnostic and treatment strategies.