Metabolic Diseases Branch and Genetics and Endocrinology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Endocr Pract. 2011 Jul-Aug;17 Suppl 3(Suppl 3):18-27. doi: 10.4158/EP11067.RA.
To review hyperparathyroid syndromes and genes.
Pertinent original studies from the literature are discussed.
Six main hyperparathyroid syndromes are recognized; 5 are from germline mutations in 4 genes-CASR, MEN1, RET, and HRPT2. Each hyperparathyroid syndrome was first described around 1965; the main gene for each syndrome was identified about 30 years later. Gene identification addressed clinical issues. (1) Testing for mutation carriers among affected probands or among unaffected relatives is more robust than prior methods, which were based on syndromal traits such as serum calcium. (2) Interpreting a gene test (RET) could guide an important intervention; other gene tests could yield useful information for patients and physicians. (3) Proving the roles of each gene (in particular, MEN1 somatic mutations) provided insights about contributions to many common tumors. (4) Clarifying molecular pathways and drugs led, for example, to the CASR-aided development of calcimimetic and calcilytic drugs. (5) Explaining novel features, such as the CASR gene encoding a membrane calcium-sensing receptor and its mutations resulting in nonsuppressed parathyroid hormone secretion uncoupled from proliferation, characterized familial hypocalciuric hypercalcemia. (6) Disclosing probands without an identifiable mutation promoted searches for other syndromal genes. Subsequently, rare multiple endocrine neoplasia type 1-like families were shown to have inactivating germline mutations, first of p27 and subsequently of p15, p18, or p21.
The next frontier in mutation detection is arriving, with possible sequencing of the whole exome or even the whole genome for 1 case or 1 tumor at an affordable cost.
综述甲状旁腺功能亢进综合征及其相关基因。
讨论相关的原始文献。
共识别出 6 种主要的甲状旁腺功能亢进综合征，其中 5 种源于 CASR、MEN1、RET 和 HRPT2 这 4 个基因的种系突变。每种甲状旁腺功能亢进综合征最早于 1965 年被描述，随后约 30 年确定了每种综合征的主要基因。基因鉴定解决了临床问题。（1）对先证者或无相关疾病亲属进行突变携带者检测，比以前基于血清钙等综合征特征的检测方法更可靠。（2）解读基因检测（RET）可指导重要干预；其他基因检测可为患者和医生提供有用信息。（3）证明每种基因（特别是 MEN1 种系突变）的作用为许多常见肿瘤的发生提供了新的认识。（4）阐明分子途径和药物作用机制，例如，CASR 有助于开发钙敏感受体激动剂和钙敏感受体拮抗剂。（5）解释新的特征，如 CASR 基因编码的膜钙敏感受体及其突变导致甲状旁腺激素分泌不依赖于增殖而被抑制，阐明家族性低钙血症性高钙血症的发病机制。（6）发现无法识别突变的先证者，促使寻找其他综合征相关基因。随后，发现少数多发性内分泌腺瘤病 1 型样家族存在种系失活突变，最初是 p27，随后是 p15、p18 或 p21。
随着成本降低，下一个检测突变的前沿技术可能是对 1 个病例或 1 个肿瘤进行整个外显子或甚至整个基因组测序。
