Investigation of Familial Isolated HPT, Parathyroid Canc

鉴定负责遗传性肿瘤综合征的基因通常提供了对控制细胞生长，增殖和信号传导的关键途径的见解。大约5%的原发性甲状旁腺功能亢进（HPT）本质上是家族性的，尽管许多致病基因仍未被识别。甲状旁腺功能亢进-下颌肿瘤综合征（HPT- jt）是一种家族性HPT综合征，常染色体显性遗传，外显率高但不完全。HPT的主要特征是HPT(90%)，包括15%的HPT- jt合并甲状旁腺癌、颌骨肿瘤（30%）、双侧肾囊肿（10%）和较少见的实体肾肿瘤。近10%的成人病例似乎是沉默的携带者。该性状与位于1q25-q31的HRPT2位点相连。代谢疾病处参与了一项国际合作努力，以确定负责1号染色体长臂上HPT-JT的基因。对26个病种进行基因分型，将1号染色体区域细化到12 cM的临界区间。利用定位候选方法，在14个HPT-JT家族的单个基因中鉴定出13种不同的杂合、种系失活突变。在48例具有囊性特征的甲状旁腺瘤的突变筛选中，发现了3个体细胞失活突变，均位于外显子1，支持了HRPT2作为肿瘤抑制因子的作用。在正常对照中没有检测到这些突变，并且预测所有突变都会导致蛋白质功能缺陷或受损。HRPT2是一个广泛表达的，进化保守的基因，编码一个531个氨基酸的预测蛋白，该蛋白被命名为parafibromin。这些发现提示HRPT2是一种肿瘤抑制基因，其失活直接参与HPT-JT易感性和一些散发性甲状旁腺肿瘤的发生。我们科最近的临床研究表明，种系HRPT2突变是家族性孤立性甲状旁腺功能亢进的罕见原因。目前的研究主要集中在HRPT2基因产物parafibromin的表达和功能上。

Identification of the genes reponsible for syndromes of inherited neoplasia frequently provides insight into critical pathways governing cellular growth, proliferation and signalling. Approximately 5% of primary hyperparathyroidism (HPT) is familial in nature, though many of the causative genes remain unrecognized. Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a familial syndrome of HPT with autosomal dominant transmission and high but incomplete penetrance. The major features are HPT (90%) including 15% of all affected by HPT-JT with parathyroid cancer, jaw tumors (30%), bilateral renal cysts (10%), and less commonly solid renal tumors. Nearly 10% of adult cases appear to be silent carriers. The trait links to the HRPT2 locus at 1q25-q31. The Metabolic Diseases Branch participated in an international collaborative effort to identify the gene responsible for HPT-JT on the long arm of chromosome 1. The region on chromosome 1 was refined to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, thirteen different heterozygous, germline, inactivating mutations were identified in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations was detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a widely expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which the name parafibromin was proposed. These findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors. Recent clinical studies in our Branch demonstrated that germline HRPT2 mutation is a rare cause of familial isolated hyperparathroidism. Current studies are focused on the expression and function of the HRPT2 gene product parafibromin.