Molecular Biology of Hereditary Diabetes Insipidus

Abstract

A nyone who passes large volumes of urine might be said to be experiencing diabetes insipidus. Years ago, the initial distinction made by physicians in evaluating patients with polyuria was whether their urine was sweet (diabetes mellitus) or not (diabetes insipidus) (1). Diabetes insipidus is a disorder characterized by the excretion of abnormally large volumes (Ͼ30 ml/kg body wt/d for adults) of dilute urine (Ͻ250 mmol/kg). This definition excludes osmotic diuresis, which occurs when excess solute is being excreted, for example, glucose in the polyuria of diabetes mellitus. Four basic defects can be involved: (1) deficient secretion of the antidiuretic hormone arginine vasopressin (AVP), which is the most common defect and is referred to as neurohypophyseal (also known to as neurogenic, central, or hypothalamic) diabetes insipidus; (2) renal insensitivity to the antidiuretic effect of AVP, which is known as nephrogenic diabetes insipidus (NDI); (3) excessive water intake that can result in polyuria, which is referred to as primary polydipsia; and (4) increased metabolism of vasopressin during pregnancy, which is referred to as gestational diabetes insipidus. The hereditary forms of diabetes insipidus account for Ͻ10% of the cases of diabetes insipidus seen in clinical practice. The purpose of this review is to examine recent developments in the understanding and molecular biology of the hereditary forms of diabetes insipidus. Here we use the gene symbols approved by the HUGO Gene Nomenclature Committee (http://www.gene.ucl.ac.uk/nomenclature) and provide OMIM entry numbers (2). Not included in this review are acquired forms of NDI; for further information, see references 3-5. Genes Involved in "Pure" Diabetes Insipidus AVPThe regulation of the release of AVP from the posterior pituitary is primarily dependent, under normal circumstances, on tonicity information relayed by osmoreceptor cells in the anterior hypothalamus (6). AVP and its corresponding carrier, neurophysin II, are synthesized as a composite precursor by the magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus (for review, see 7). The precursor is packaged into neurosecretory granules and transported axonally in the stalk of the posterior pituitary. En route to the neurohypophysis, the precursor is processed into the active hormone. Prepro-vasopressin has 164 amino acids and is encoded by the 2.5-kb AVP gene located in chromosome region 20p13 (8,9). The AVP gene (coding for AVP and neurophysin II) and the OXT gene (coding for oxytocin and neurophysin I) are located in the same chromosome region, at a very short distance from each other (12 kb in humans) in head-to-head orientation. Data from transgenic mouse studies indicate that the intergenic region between the OXT and the AVP genes contains the critical enhancer sites for cell-specific expression in the magnocellular neurons (7). It is phylogenetically interesting to note that cis and trans components of this specific cellular expression have been conserved bet...

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

“…Nephrogenic diabetes insipidus (NDI) is commonly caused by mutations of the vasopressin 2 receptor (V2R) gene; a specific therapy for this disease is lacking (30,31). We explored the therapeutic potential of sPRR-His in a mouse model of NDI induced with a V2R antagonist, OPC.…”

G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue in Vivo

“…Information condensed as follows: rhodopsin (Stojanovic and Hwa, 2002;Mendes et al, 2005;Tao, 2006); V2R (Bernier et al, 2004a,b;Fujiwara and Bichet, 2005;Bichet, 2006;Boson et al, 2006;Robben and Deen, 2007;Robben et al, 2006); GnRHR (Beranova et al, 2001;Janovick et al, 2003a;Ulloa-Aguirre et al, 2004a,b); CaR (Brown, 2007;Huang and Breitwieser, 2007); LHR (Gromoll et al, 2002;Martens et al, 2002;Huhtaniemi and Themmen, 2005;Piersma et al, 2007); FSHR (Rannikko et al, 2002;Meduri et al, 2003;Huhtaniemi and Themmen, 2005); TSHR (Biebermann et al, 1997;Costagliola et al, 1999;Tonacchera et al, 2000Tonacchera et al, , 2004Calebiro et al, 2005;Davies et al, 2005); E-BR (Tanaka et al, 1998;Fuchs et al, 2001;Chen et al, 2006;Tao, 2006); MC1R-4R (Beaumont et al, 2005;Clark et al, 2005;Govaerts et al, 2005;Tao, 2005Tao, , 2006Farooqi and O´Rahilly, 2006;Hinney et al, 2006;Lubrano-Berthelier et al, 2006;Alharbi et al, 2007;Lin et al, 2007); and CCR5 receptor (Lede...…”

“…Agonists and antagonists (peptide and nonpeptide) seem to prefer a common V2R compartment for docking (Czaplewski et al, 1998a,b (Czaplewski et al, 1998b). Nearly 188 inactivating mutations of the V2R causing X-linked diabetes insipidus have been described previously (Fujiwara and Bichet, 2005;Bichet, 2006;Boson et al, 2006); the vast majority of these mutations correspond to the so-called type 2 V2R mutant receptor (Bichet, 2006;. Furthermore, 89 of these 184 mutations are missense mutations likely to result in misfolded proteins that are trapped in the ER and are unable to reach the basolateral cell surface to engage the antidiuretic hormone arginine-vasopressin (Bichet, 2006).…”

Novel mutations underlying nephrogenic diabetes insipidus in Arab families

“…1,2 Congenital nephrogenic diabetes insipidus (CNDI) is an inherited disorder, caused by mutations in AVPR2 or AQP2. [3][4][5][6][7] NDI patients are unable to increase urinary osmolality, which remains Ͻ200 mosmol/kg H 2 O (normal values are Ͼ805 mosmol/kg H 2 O).…”