Background/Aim: Variability in the severity and age at onset of autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) may be associated with certain types of variants in the arginine vasopressin (AVP) gene. In this study, we aimed to describe a large family with an apparent predominant female occurrence of polyuria and polydipsia and to determine the underlying cause. Methods: The family members reported their family demography and symptoms. Two subjects were diagnosed by fluid deprivation and dDAVP challenge tests. Eight subjects were tested genetically. The identified variant along with 3 previously identified variants in the AVP gene were investigated by heterologous expression in a human neuronal cell line (SH-SY5Y). Results: Both subjects investigated clinically had a partial neurohypophyseal diabetes insipidus phenotype. A g.276_278delTCC variant in the AVP gene causing a Ser18del deletion in the signal peptide (SP) of the AVP preprohormone was perfectly co-segregating with the disease. When expressed in SH-SY5Y cells, the Ser18del variant along with 3 other SP variants (g.227G>A, Ser17Phe, and Ala19Thr) resulted in reduced AVP mRNA, impaired AVP secretion, and partial AVP prohormone degradation and retention in the endoplasmic reticulum. Impaired SP cleavage was demonstrated directly in cells expressing the Ser18del, g.227G>A, and Ala19Thr variants, using state-of-the-art mass spectrometry. Conclusion: Variants affecting the SP of the AVP preprohormone cause adFNDI with variable phenotypes by a mechanism that may involve impaired SP cleavage combined with effects at the mRNA, protein, and cellular level.

1.
Robertson GL: Diabetes insipidus. Endocrinol Metab Clin North Am 1995;24:549-572.
2.
Babey M, Kopp P, Robertson GL: Familial forms of diabetes insipidus: clinical and molecular characteristics. Nat Rev Endocrinol 2011;7:701-714.
3.
Christensen JH, Robertson GL: Translational Endocrinology and Metabolism: Posterior Pituitary Update. Chevy Chase, The Endocrine Society, 2012.
4.
Olias G, Richter D, Schmale H: Heterologous expression of human vasopressin-neurophysin precursors in a pituitary cell line: defective transport of a mutant protein from patients with familial diabetes insipidus. DNA Cell Biol 1996;15:929-935.
5.
Ito M, Jameson JL, Ito M: Molecular basis of autosomal dominant neurohypophyseal diabetes insipidus. Cellular toxicity caused by the accumulation of mutant vasopressin precursors within the endoplasmic reticulum. J Clin Invest 1997;99:1897-1905.
6.
Nijenhuis M, Zalm R, Burbach JPH: Mutations in the vasopressin prohormone involved in diabetes insipidus impair endoplasmic reticulum export but not sorting. J Biol Chem 1999;274:21200-21208.
7.
Christensen JH, Siggaard C, Corydon TJ, Robertson GL, Gregersen N, Bolund L, et al: Impaired trafficking of mutated AVP prohormone in cells expressing rare disease genes causing autosomal dominant familial neurohypophyseal diabetes insipidus. Clin Endocrinol (Oxf) 2004;60:125-136.
8.
Siggaard C, Christensen JH, Corydon TJ, Rittig S, Robertson GL, Gregersen N, et al: Expression of three different mutations in the arginine vasopressin gene suggests genotype-phenotype correlation in familial neurohypophyseal diabetes insipidus kindreds. Clin Endocrinol (Oxf) 2005;63:207-216.
9.
Ito M, Yu RN, Jameson JL: Mutant vasopressin precursors that cause autosomal dominant neurohypophyseal diabetes insipidus retain dimerization and impair the secretion of wild-type proteins. J Biol Chem 1999;274:9029-9037.
10.
Rittig S, Robertson GL, Siggaard C, Kovács L, Gregersen N, Nyborg J, et al: Identification of 13 new mutations in the vasopressin-neurophysin II gene in 17 kindreds with familial autosomal dominant neurohypophyseal diabetes insipidus. Am J Hum Genet 1996;58:107-117.
11.
Christensen JH, Rittig S: Familial neurohypophyseal diabetes insipidus - an update. Semin Nephrol 2006;26:209-223.
12.
Russell TA, Ito M, Ito M, Yu RN, Martinson FA, Weiss J, et al: A murine model of autosomal dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-producing neurons. J Clin Invest 2003;112:1697-1706.
13.
Hayashi M, Arima H, Ozaki N, Morishita Y, Hiroi M, Ozaki N, et al: Progressive polyuria without vasopressin neuron loss in a mouse model for familial neurohypophysial diabetes insipidus. Am J Physiol Regul Integr Comp Physiol 2009;296:R1641-R1649.
14.
Arima H, Morishita Y, Hagiwara D, Hayashi M, Oiso Y: Endoplasmic reticulum stress in vasopressin neurons of familial diabetes insipidus model mice: aggregate formation and mRNA poly(A) tail shortening. Exp Physiol 2014;99:66-71.
15.
Hiroi M, Morishita Y, Hayashi M, Ozaki N, Sugimura Y, Nagasaki H, et al: Activation of vasopressin neurons leads to phenotype progression in a mouse model for familial neurohypophysial diabetes insipidus. Am J Physiol Regul Integr Comp Physiol 2010;298:R486-R493.
16.
Morishita Y, Arima H, Hiroi M, Hayashi M, Hagiwara D, Asai N, et al: Poly(A) tail length of neurohypophysial hormones is shortened under endoplasmic reticulum stress. Endocrinology 2011;152:4846-4855.
17.
Hagiwara D, Arima H, Morishita Y, Wenjun L, Azuma Y, Ito Y, et al: Arginine vasopressin neuronal loss results from autophagy-associated cell death in a mouse model for familial neurohypophysial diabetes insipidus. Cell Death Dis 2014;5:e1148.
18.
Azuma Y, Hagiwara D, Lu W, Morishita Y, Suga H, Goto M, et al: Activating transcription factor 6α is required for the vasopressin neuron system to maintain water balance under dehydration in male mice. Endocrinology 2014;155:4905-4914.
19.
Lindenthal V, Mainberger A, Morris-Rosendahl DJ, Löning L, Mayer W, Müller HL: Dilatative uropathy as a manifestation of neurohypophyseal diabetes insipidus due to a novel mutation in the arginine vasopressin-neurophysin-II gene. Klin Padiatr 2013;225:407-412.
20.
Perrotta S, Iorgi ND, Ragione FD, Scianguetta S, Borriello A, Allegri AEM, et al: Early-onset central diabetes insipidus is associated with de novo arginine vasopressin-neurophysin II or Wolfram syndrome 1 gene mutations. Eur J Endocrinol 2015;172:461-472.
21.
Ilhan M, Tiryakioglu NO, Karaman O, Coskunpinar E, Yildiz RS, Turgut S, et al: A novel AVP gene mutation in a Turkish family with neurohypophyseal diabetes insipidus. J Endocrinol Invest 2016;39:285-290.
22.
Beuret N, Rutishauser J, Bider MD, Spiess M: Mechanism of endoplasmic reticulum retention of mutant vasopressin precursor caused by a signal peptide truncation associated with diabetes insipidus. J Biol Chem 1999;274:18965-18972.
23.
Siggaard C, Rittig S, Corydon TJ, Andreasen PH, Jensen TG, Andresen BS, et al: Clinical and molecular evidence of abnormal processing and trafficking of the vasopressin preprohormone in a large kindred with familial neurohypophyseal diabetes insipidus due to a signal peptide mutation. J Clin Endocrinol Metab 1999;84:2933-2941.
24.
Birk J, Friberg MA, Prescianotto-Baschong C, Spiess M, Rutishauser J: Dominant pro-vasopressin mutants that cause diabetes insipidus form disulfide-linked fibrillar aggregates in the endoplasmic reticulum. J Cell Sci 2009;122:3994-4002.
25.
Repaske DR, Medlej R, Gültekin EK, Krishnamani MR, Halaby G, Findling JW, et al: Heterogeneity in clinical manifestation of autosomal dominant neurohypophyseal diabetes insipidus caused by a mutation encoding Ala-1→Val in the signal peptide of the arginine vasopressin/neurophysin II/copeptin precursor. J Clin Endocrinol Metab 1997;82:51-56.
26.
Emmeluth C, Drummer C, Gerzer R, Bie P: Natriuresis in conscious dogs caused by increased carotid [Na+] during angiotensin II and aldosterone blockade. Acta Physiol Scand 1994;151:403-411.
27.
Bie P, Sandgaard NC: Determinants of the natriuresis after acute, slow sodium loading in conscious dogs. Am J Physiol Regul Integr Comp Physiol 2000;278:R1-R10.
28.
Jendle J, Christensen JH, Kvistgaard H, Gregersen N, Rittig S: Late-onset familial neurohypophyseal diabetes insipidus due to a novel mutation in the AVP gene. Clin Endocrinol (Oxf) 2012;77:586-592.
29.
Christensen JH, Siggaard C, Corydon TJ, deSanctis L, Kovács L, Robertson GL, et al: Six novel mutations in the arginine vasopressin gene in 15 kindreds with autosomal dominant familial neurohypophyseal diabetes insipidus give further insight into the pathogenesis. Eur J Hum Genet 2003;12:44-51.
30.
Heid CA, Stevens J, Livak KJ, Williams PM: Real time quantitative PCR. Genome Res 1996;6:986-994.
31.
Andersen CL, Jensen JL, Ørntoft TF: Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res 2004;64:5245-5250.
32.
Kovalevich J, Langford D: Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology. Methods Mol Biol 2013;1078:9-21.
33.
Christensen JH, Siggaard C, Corydon TJ, Robertson GL, Gregersen N, Bolund L, et al: Differential cellular handling of defective arginine vasopressin (AVP) prohormones in cells expressing mutations of the AVP gene associated with autosomal dominant and recessive familial neurohypophyseal diabetes insipidus. J Clin Endocrinol Metab 2004;89:4521-4531.
34.
Ito M, Mori Y, Oiso Y, Saito H: A single base substitution in the coding region for neurophysin II associated with familial central diabetes insipidus. J Clin Invest 1991;87:725-728.
35.
van den Akker EL, de Groot MR, Abbes AP, Bruggeman EJ, Franken AA, Engel H: Identification of a new mutation (CysII6Gly) in a family with neurogenic diabetes insipidus (in Dutch). Ned Tijdschr Geneeskd 2000;144:941-945.
36.
Bullmann C, Kotzka J, Grimm T, Heppner C, Jockenhövel F, Krone W, et al: Identification of a novel mutation in the arginine vasopressin-neurophysin II gene in familial central diabetes insipidus. Exp Clin Endocrinol Diabetes 2002;110:134-137.
37.
Rittig S, Siggaard C, Ozata M, Yetkin I, Gregersen N, Pedersen EB, et al: Autosomal dominant neurohypophyseal diabetes insipidus due to substitution of histidine for tyrosine2 in the vasopressin moiety of the hormone precursor. J Clin Endocrinol Metab 2002;87:3351-3355.
38.
Santiprabhob J, Browning J, Repaske D: A missense mutation encoding Cys73Phe in neurophysin II is associated with autosomal dominant neurohypophyseal diabetes insipidus. Mol Genet Metab 2002;77:112-118.
39.
Kanemitsu N, Kawauchi A, Nishida M, Tanaka Y, Mizutani Y, Shirahama S, et al: Familial central diabetes insipidus detected by nocturnal enuresis. Pediatr Nephrol 2002;17:1063-1065.
40.
Rutishauser J, Kopp P, Gaskill MB, Kotlar TJ, Robertson GL: Clinical and molecular analysis of three families with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel and recurrent mutations in the vasopressin-neurophysin II gene. Eur J Endocrinol 2002;146:649-656.
41.
Boson WL, Sarubi JC, D'Alva CB, Friedman E, Faria D, De Marco L, et al: A signal peptide mutation of the arginine vasopressin gene in monozygotic twins. Clin Endocrinol (Oxf) 2003;58:108-110.
42.
Lek M, Karczewski K, Minikel E, Samocha K, Banks E, et al; Exome Aggregation Consortium: Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016;536:285-291.
43.
Robertson GL: The use of vasopressin assays in physiology and pathophysiology. Semin Nephrol 1994;14:368-383.
44.
Robertson GL: Diabetes insipidus: differential diagnosis and management. Best Pract Res Clin Endocrinol Metab 2016;30:205-218.
45.
Francis SM, Kistner-Griffin E, Yan Z, Guter S, Cook EH, Jacob S: Variants in adjacent oxytocin/vasopressin gene region and associations with ASD diagnosis and other autism related endophenotypes. Front Neurosci 2016;10:195.
46.
Chooi KF, Carter DA, Murphy D: Decrease in hypothalamic vasopressin mRNA poly(A) tail length following physiological stimulation. Cell Mol Neurobiol 1992;12:557-567.
47.
Svane PC, Thorn NA, Richter D, Mohr E: Effect of hypoosmolality on the abundance, poly(A) tail length and axonal targeting of arginine vasopressin and oxytocin mRNAs in rat hypothalamic magnocellular neurons. FEBS Lett 1995;373:35-38.
48.
Carter DA, Murphy D: Rapid changes in poly(A) tail length of vasopressin and oxytocin mRNAs form a common early component of neurohypophyseal peptide gene activation following physiological stimulation. Neuroendocrinology 1991;53:1-6.
49.
Carrazana EJ, Pasieka KB, Majzoub JA: The vasopressin mRNA poly(A) tract is unusually long and increases during stimulation of vasopressin gene expression in vivo. Mol Cell Biol 1988;8:2267-2274.
50.
Shao S, Hegde RS: Target selection during protein quality control. Trends Biochem Sci 2016;41:124-137.
51.
Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA, et al: An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 2012;489:391-399.
52.
Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al: Genome-wide atlas of gene expression in the adult mouse brain. Nature 2007;445:168-176.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.