PATHOGENESIS AND PATHOPHYSIOLOGY OF FAMILIAL NEUROHYPOPHYSEAL DIABETES

这项研究的目的是获得更多的临床和分子遗传学数据，以检验家族性神经垂体型尿崩症(FNDI)是由于血管加压素-神经物理素II基因编码区的突变所致，该基因指导突变的前激素原的产生，由于不能有效地折叠和处理，该前激素原积累在大细胞神经元中并破坏它。这些研究将在至少14个已知或推定FNDI正在隔离的美国家庭的所有受影响和未受影响的成员中进行。受试者将每隔一至五年住进临床研究中心，在基础条件下和在禁液/高渗盐水或水负荷/高渗盐水输注试验中，测量液体摄入量和尿量、血浆电解质、血浆和尿液加压素、尿水通道蛋白II和异常形式的“大血管加压素”。受试者还将接受垂体-下丘脑区的核磁共振检查，并采集血液进行血管加压素-神经物理蛋白基因的测序。受影响的受试者将接受去氨加压素(DDAVP)的治疗试验。少数经历尿崩症自然缓解的受试者也可以接受催产素或加压素拮抗剂的短期输注，以确定是否发生尿液稀释。

The objective of this study is to obtain additional clinical and molecular genetic data to test the hypothesis that familial neurohypophyseal diabetes insipidus (FNDI) is due to mutations in the coding region of the vasopressin-neurophysin II gene that directs the production of a mutant preprohormone that accumulates in and destroys magnocellular neurons because it can not be folded and processed efficiently. The studies will be performed in all consenting affected and unaffected members of at least 14 American kindreds in which FNDI is known or presumed to be segregating. The subjects will be admitted to the Clinical Research Center at 1 to 5 year intervals for measurements of fluid intake and urine output, plasma electrolytes, plasma and urinary vasopressin, urine aquaporin II and abnormal forms of "big vasopressin" under basal conditions and during a fluid deprivation/hypertonic saline infusion or water load/hypertonic saline infusion test. Subjects will also undergo MRI of the pituitary-hypothalamic area and have blood collected for sequencing of the vasopressin-neurophysin gene. Affected subjects will undergo a therapeutic trial of desmopressin (DDAVP). A few subjects who undergo spontaneous remissions of their diabetes insipidus may also receive short infusions of oxytocin or vasopressin antagonists to determine if urinary dilution occurs.