Familial Isolated HPT, Parathyroid Cancer, HPT-JT Syndro

家族性孤立性 HPT、甲状旁腺癌、HPT-JT 综合征

• 批准号: 7152640
• 负责人: WILLIAM F SIMONDS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7152640
• 关键词: chromosomes; disease /disorder classification; family genetics; gene expression; gene mutation; genetic disorder; genetic screening; head /neck neoplasm; human subject; hypercalcemia; hyperparathyroidism; jaw; multiple endocrine neoplasia; neoplasm /cancer epidemiology; neoplasm /cancer genetics; oral pharyngeal neoplasm; parathyroid neoplasms; patient oriented research; syndrome; tumor suppressor genes

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. In previous clinical studies from our Branch we 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.

对遗传性肿瘤综合征相关基因的鉴定，常常为了解控制细胞生长、增殖和信号传导的关键途径提供帮助。大约5%的原发性甲状旁腺功能亢进症（HPT）是家族性的，尽管许多致病基因仍未被认识。高甲状旁腺-颌骨肿瘤综合征（HPT-JT）是一种常染色体显性遗传的家族性HPT综合征。主要特征是HPT（90%），包括15%的HPT-JT患者，包括甲状旁腺癌、颌骨肿瘤（30%）、双侧肾囊肿（10%）和不太常见的实体性肾肿瘤。近10%的成人病例似乎是沉默的携带者。该性状与1 q25-q31的HRPT 2基因座连锁。代谢疾病分支参与了一项国际合作努力，以确定1号染色体长臂上导致HPT-JT的基因。1号染色体上的区域被细化到12 cM的临界区间，通过基因分型在26个受影响的kinetics。使用位置候选人的方法，13个不同的杂合，种系，失活突变被确定在一个单一的基因在14个家庭与HPT-JT。HRPT 2作为肿瘤抑制因子的建议作用得到了48例具有囊性特征的甲状旁腺腺瘤突变筛查的支持，该筛查确定了3个体细胞失活突变，均位于外显子1。在正常对照中未检测到这些突变，并且预测所有这些突变都会导致蛋白质功能缺陷或受损。HRPT 2是一种广泛表达的进化上保守的基因，编码一种预测的531个氨基酸的蛋白质，因此提出了副纤维蛋白的名称。这些研究结果表明，HRPT 2是一种肿瘤抑制基因，其失活直接参与HPT-JT的易感性和一些散发性甲状旁腺肿瘤的发展。在我们分支以前的临床研究中，我们证明了生殖系HRPT 2突变是家族性孤立性肥大性关节炎的罕见原因。目前的研究集中在HRPT 2基因产物parafibromin的表达和功能。