PDF(Pubmed)
Abstract：
Hyperparathyroidism jaw-tumor syndrome is an autosomal dominant disorder caused by mutations in the CDC73/HRPT2 tumor suppressor gene, encoding parafibromin, and manifesting benign or malignant parathyroid tumors, ossifying jaw fibromas, uterine tumors, and kidney lesions. Sporadic parathyroid carcinomas also frequently exhibit inactivating CDC73 mutations and loss of parafibromin. To study the role of CDC73 in parathyroid cell proliferation in vivo, we generated mice with a parathyroid-specific deletion of Cdc73. Homozygous knockout mice on a mixed B6/129/CD1 background had decreased serum calcium and PTH and smaller parathyroid glands compared with heterozygous or wild-type littermates, whereas homozygous Cdc73-null mice on other backgrounds exhibited no abnormalities in parathyroid gland function or development. No hypercalcemia or parathyroid hypercellularity was observed in mice of any background examined at any age. Thus, although postnatally acquired complete loss of CDC73 causes parathyroid cell proliferation and hyperparathyroidism, such as seen in human hyperparathyroidism jaw-tumor syndrome, our results suggest that earlier, developmentally imposed complete loss of Cdc73 can cause a primary defect in parathyroid gland structure/function in a strain-dependent manner. This striking disparity in parathyroid phenotype related to genetic background offers a unique opportunity in an in vivo model system to precisely dissect and identify the responsible molecular mechanisms.
摘要：
甲状旁腺功能亢进颌骨肿瘤综合征是由CDC73/HRPT2肿瘤抑制基因突变引起的常染色体显性疾病，编码纤维旁蛋白，表现为良性或恶性甲状旁腺肿瘤，骨化颌骨纤维瘤,子宫肿瘤,和肾脏病变。散发性甲状旁腺癌也经常表现出CDC73突变失活和纤维旁蛋白丢失。探讨CDC73在体内甲状旁腺细胞增殖中的作用,我们产生了甲状旁腺特异性Cdc73缺失的小鼠。与杂合或野生型同窝相比，在混合B6/129/CD1背景下的纯合敲除小鼠的血清钙和PTH降低，甲状旁腺较小，而纯合的Cdc73-null小鼠在其他背景下没有表现出甲状旁腺功能或发育异常。在任何年龄检查的任何背景的小鼠中均未观察到高钙血症或甲状旁腺细胞过多。因此，尽管出生后获得的CDC73完全丢失会导致甲状旁腺细胞增殖和甲状旁腺功能亢进，如在人类甲状旁腺功能亢进颌骨肿瘤综合征中所见，我们的结果表明，更早，发育施加的Cdc73完全丧失可能以应变依赖性方式导致甲状旁腺结构/功能的原发性缺陷。与遗传背景相关的甲状旁腺表型的这种惊人差异为体内模型系统提供了独特的机会，可以精确解剖和鉴定负责的分子机制。
