Molecular Definition of Pseudohypoparathyroidism

描述(由申请人提供)：受 假性Ib型甲状旁腺功能减退症(PHP-Ib)表现不同程度的 甲状旁腺素抵抗引起的低钙血症和高磷血症。这些人 然而，没有证据表明奥尔布赖特遗传性骨营养不良症(Aho)和 因此与假性甲状旁腺功能减退症Ia型(PHP-Ia)患者不同 假性假性甲状旁腺功能减退症(PPHP)。因为选择性抗药性 一种激素，甲状旁腺素，PHP-Ib最初被认为是由 甲状旁腺素受体的突变，现在被称为甲状旁腺素/甲状旁腺素受体。 然而，我们的实验室和其他研究小组排除了这种突变。更多 重要的是，PTH/PTHrP受体突变，激活或失活， 现在已知会导致矿物质离子调节的严重异常 动态平衡和骨骼发育，这与通常非常温和的 在PHP-Ib患者中观察到的实验室异常。这表明， 遗传缺陷存在于一种未知的基因中，该基因具有显著的调节作用 PTH/PTHrP受体和/或下游信号蛋白的表达。 因此进行了全基因组扫描，发现了 染色体20Q 13.3的常染色体显性形式的PHP-Ib，它包括GNAS1 在它的端粒边界。这些研究进一步表明，这种疾病是 父系遗传，即荷尔蒙抵抗只传递给下一个 如果疾病相关等位基因是从一个专有基因遗传而来的 女性携带者。这种遗传方式类似于在亲属中发现的 在PHP-Ia/PPHP中，由杂合子引起的两种相关疾病， 编码Gs-α的13个GNAS1外显子中的一个外显子的突变失活。 除了编码无处不在的信号蛋白外，GNAS1还至少产生了 四个额外的编码和非编码/非翻译的文字记录，以及 其中几个转录本的启动子区域经历亲本专一性 甲基化，从而导致失活。这些表观遗传变化中的一个，即丢失 到目前为止，A/B外显子(也称为外显子1A或1‘)的甲基化 已被证明专门发生在受PHP-Ib影响的患者中。然而， 导致这种甲基化异常的基因突变，并可能导致 PTH抗性似乎位于表观遗传学的上游至少50kb。 缺陷，很可能是在内含子调控区域。我们现在建议 通过核苷酸序列分析鉴定该基因突变(S)， 额外的连锁研究，或转基因动物的体内方法，以及 探讨肾组织甲状旁腺素抵抗的分子机制(S) 大脑皮层。

DESCRIPTION (provided by applicant): Patients affected by pseudohypoparathyroidism type Ib (PHP-Ib) display variable degrees of hypocalcemia and hyperphosphatemia due to PTH-resistance. These individuals show, however, no evidence for Albright's hereditary osteodystrophy (AHO) and are thus distinct from patients with pseudohypoparathyroidism type Ia (PHP-Ia) and pseudo-pseudohypoparathyroidism (pPHP). Because of the selective resistance to a single hormone, PTH, PHP-Ib was initially thought to be caused by mutations in the PTH-receptor, now referred to as the PTH/PTHrP receptor. However, our laboratory and other groups excluded such mutations. More importantly, PTH/PTHrP receptor mutations, either activating or inactivating, are now known to lead to severe abnormalities in the regulation of mineral ion homeostasis and bone development, which is different from the often very mild laboratory abnormalities observed in PHP-Ib patients. This suggested that the genetic defect lies in a yet unknown gene with a prominent role in regulating the expression of the PTH/PTHrP receptor and/or down-stream signaling proteins. A genome-wide scan was therefore conducted and revealed linkage of the autosomal dominant form of PHP-Ib to chromosome 20q 13.3, which comprises GNAS1 at its telomeric boundary. These studies furthermore showed that the disease is paternally imprinted, i.e. hormonal resistance is only transmitted to the next generation if the disease-associated allele is inherited from an obligate female carrier. This mode of inheritance is similar to the findings in kindreds with PHP-Ia/pPHP, two related disorders that are caused by heterozygous, inactivating mutations in one of the thirteen GNAS1 exons encoding Gs-alpha. Besides encoding the ubiquitous signaling protein, GNAS1 gives rise to at least four additional coding and non-coding/non-translated transcripts, and the promoter region for several of these transcripts undergoes parent-specific methylation and thus inactivation. One of these epigenetic changes, i.e. a loss of methylation at the A/B exon (also referred to exon 1A or 1'), has thus far been shown to occur specifically in patients affected by PHP-Ib. However, the genetic mutation leading to this methylation abnormality and presumably to PTH-resistance appears to be located at least 50 kb up-stream of the epigenetic defect, most likely in an intronic regulatory region. We now propose to identify this genetic mutation(s) through nucleotide sequence analysis, additional linkage studies, or an in vivo approach with transgenic animals, and to explore the molecular mechanism(s) underlying PTH-resistance in the renal cortex.