X-linked recessive familial neuro-hypophyseal diabetes insipidus

摘要尿崩症（DI）患者表现为持续口渴、渴渴和低渗多尿。该疾病由几种不同的病因引起，适当的诊断检查是区分各种形式的必要条件，包括神经垂体性、肾源性、妊娠性和多饮性DI，也称为原发性多饮。一个完整的、正确执行的液体剥夺/DDAVP测试可以建立正确的诊断。在过去的二十年中，一些遗传形式的DI已经在分子水平上被表征。神经垂体形式是由位于染色体20p13上的AVP- npii基因突变引起的，该基因编码抗利尿激素抗利尿激素（AVP），通常以常染色体显性方式遗传。临床上，AVP分泌不足在出生后几个月到几年变得明显，其严重程度从部分到几乎完全发展。由于细胞内保留和突变前体的细胞毒性作用，产生大细胞神经垂体神经元的AVP变性可以解释出生后的进展。进行性AVP缺乏通常伴随着T1加权磁共振成像上垂体后叶亮点信号消失。极少情况下，这种疾病是由编码非肽AVP的AVP- npii基因区域的双等位基因突变引起的。我们发现了一种以x连锁隐性方式遗传的新型神经垂体DI，并在Xq28上建立了约8厘摩根间隔的联系。这种形式的神经垂体DI不能用AVP-NPII基因突变来解释。本建议中概述的实验旨在改进链接区域，并使用高通量方法将候选区域提交给序列分析。这项研究的结果有望为AVP的加工提供新的基础见解，从而为人类的水代谢生理学提供新的见解。

DESCRIPTION (provided by applicant): Abstract Patients with diabetes insipidus (DI) present with persistent thirst, polydipsia, and hypotonic polyuria. The disorder is caused by several distinct etiologies and an appropriate diagnostic work-up is essential for the distinction of the various forms that include neurohypophyseal, nephrogenic, gestational, and polydipsic DI, which is also referred to as primary polydipsia. A complete, properly performed fluid deprivation/DDAVP test permits establishing the correct diagnosis. Several genetic forms of DI have been characterized at the molecular level during the last two decades. The neurohypophyseal form is caused by mutations in the AVP-NPII gene located on chromosome 20p13, which encodes the antidiuretic hormone vasopressin (AVP), and is usually inherited in an autosomal dominant fashion. Clinically, the deficiency in AVP secretion becomes apparent several months to years after birth and progresses in severity from partial to nearly complete. The postnatal progression is explained by degeneration of the AVP producing magnocellular neurohypophyseal neurons due to intracellular retention and a cytotoxic effect of the mutated precursor. The progressive deficiency in AVP is typically accompanied by the disappearance of the posterior pituitary bright spot signal on T1- weighted magnetic resonance imaging. Rarely, the disorder is caused by biallelelic mutations in the region of the AVP-NPII gene that encodes the nonapeptide AVP. We have identified a novel form of neurohypophyseal DI that is inherited in an X-linked recessive manner, and have established linkage to an ~8 centiMorgan interval on Xq28. This form of neurohypophyseal DI can not be explained by mutations in the AVP-NPII gene. The experiments outlined in this proposal aim at refining the linked region and to submit the candidate region to sequence analysis using a high-throughput approach. The results of this study are expected to provide novel fundamental insights into processing of AVP and thereby the physiology of water metabolism in humans. PUBLIC HEALTH RELEVANCE: Narrative Summary Normal water balance is essential for a normal function of the body and includes retention of water in the kidney, which is, in part, regulated by a hormone called anti-diuretic hormone (ADH), or vasopressin (AVP). We have identified a family with several males who lack this hormone and therefore void very large volumes of urine. This proposal aims at finding the underlying genetic defect because understanding of the defect at the molecular level could provide important insights into normal and abnormal water metabolism in humans.