X-linked recessive familial neuro-hypophyseal diabetes insipidus

X连锁隐性家族性神经垂体尿崩症

• 批准号: 7712585
• 负责人: PETER Andreas KOPP
• 金额: $ 7.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7712585
• 关键词: 20p13; AVPR2 gene; Affect; Birth; Brain; Central Diabetes Insipidus; Chromosomes; Code; Copy Number Polymorphism; Custom; DNA; Defect; Diabetes Insipidus; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Diuretics; Emulsions; Equilibrium; Etiology; Family; Family member; Gene Mutation; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Hormones; Human; Individual; Inherited; Kidney; Link; Liquid substance; Magnetic Resonance Imaging; Metabolism; Microsatellite Repeats; Modification; Molecular; Mutate; Mutation; Neurons; Nucleic Acid Regulatory Sequences; Optic Atrophy; Patients; Phenotype; Physiology; Polydipsia; Polyuria; Posterior Pituitary Gland; Process; Publishing; Receptor Gene; Sequence Analysis; Severities; Signal Transduction; Solid; Spottings; System; Testing; Thirst; Tissues; Urine; Vasopressins; Water; Weight; Wolfram Syndrome; Work; Xq28; abstracting; aquaporin-2; base; cytotoxic; deafness; density; deprivation; design; insight; interest; magnocellular; male; novel; postnatal; public health relevance; receptor; research study; segregation

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.

描述（由申请人提供）：摘要尿崩症（DI）患者表现为持续口渴、烦渴和低渗性多尿。这种疾病是由几种不同的病因引起的，适当的诊断检查对于区分各种形式是必不可少的，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测试允许建立正确的诊断。在过去的二十年中，DI的几种遗传形式已经在分子水平上得到了表征。神经垂体形式是由位于染色体20 p13上的AVP-NPII基因突变引起的，该基因编码抗利尿激素血管加压素（AVP），并且通常以常染色体显性方式遗传。临床上，AVP分泌不足在出生后数月至数年变得明显，并且严重程度从部分进展到几乎完全。出生后的进展是由于细胞内滞留和突变的前体的细胞毒性作用的AVP生产大细胞神经垂体神经元的变性解释。AVP的进行性缺乏通常伴随着T1加权磁共振成像上垂体后叶亮点信号的消失。很少，这种疾病是由编码九肽AVP的AVP-NPII基因区域的双等位基因突变引起的。我们已经确定了一种新的形式的神经垂体DI是遗传在一个X-连锁隐性方式，并已建立连锁到一个8 centiMorgan间隔Xq 28。这种形式的神经垂体DI不能用AVP-NPII基因突变来解释。本提案中概述的实验旨在细化连接区域，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的加工提供新的基本见解，从而为人类的水代谢生理学提供新的基本见解。 公共卫生关系：正常的水平衡对于身体的正常功能是必不可少的，包括肾脏中的水潴留，这部分是由称为抗利尿激素（ADH）或加压素（AVP）的激素调节的。我们已经确定了一个家庭，有几个男性缺乏这种激素，因此排尿量非常大。这项建议旨在找到潜在的遗传缺陷，因为在分子水平上了解缺陷可以为人类正常和异常的水代谢提供重要的见解。