The Novel Ser18del AVP Variant Causes Inherited Neurohypophyseal Diabetes Insipidus by Mechanisms Shared with Other Signal Peptide Variants

Abstract

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.

A Novel Synonymous Variant in the <b><i>AVP</i></b> Gene Associated with Autosomal Dominant Familial Neurohypophyseal Diabetes Insipidus Causes Partial RNA Missplicing

“…An explanation could be that both WT and variant AVP prohormones are intrinsically prone to accumulate intracellularly. This notion is supported by the fact that, in a recent study based on mass spectrometry analysis, we identified a partial faulty initiation of translation when expressing WT AVP cDNA in neuroblastoma SH-SY5T cells [5]. Alternatively, or in combination with the consequences of faulty translation, the observed ER retention of AVP prohormone might occur as a result of overexpression of minigene-based AVP.…”

“…1): exon 1 (170 bp) encodes the signal peptide, the AVP nonapeptide, and the N-terminal part of the carrier protein neurophysin II (NPII); exon 2 (202 bp) encodes the central, highly conserved region of NPII; and exon 3 (247 bp) encodes the C-terminal portion of NPII and the glycopeptide copeptin [3,4]. To date, more than 70 variants of the AVP gene have been associated with adFNDI [5]. All missense variants identified have been shown or deduced to have an effect on proper folding of the final protein.…”

Central Diabetes Insipidus Caused by Arginine Vasopressin Gene Mutation: Report of a Novel Mutation and Review of Literature

“…One is a large deletion involving the regulatory sequences in intergenic region between the AVP and the oxytocin gene and the majority of the AVP gene (10.396 base pair deletion) [5]. Another special case is the variant Ser18del (g.276_278delTCC), which seems to cause variable phenotypes with mainly females reporting symptoms [51]. In addition, c.322 + 1delG mutation is predicted to cause retention of intron 2 during splicing [37].…”

“…FNDI accounts for less than 10 % of diabetes insipidus cases seen in clinical practice [50], and is, with only a few exceptions, transmitted by autosomal dominant inheritance due to variants in one allele of the AVP gene [51]. The clinical occurrence of signs and symptoms is between the first and sixth year of life [40].…”

A Partial Phenotype of adFNDI Related to the Signal Peptide c.55G>A Variant of the AVP Gene

“…The mutation pattern of the AVP gene, initiating the pathogenic cascade of events in adFNDI, determines the accumulation of misfolded (or unfolded) AVP precursor proteins in the ER, causing ER stress and progressive degeneration of vasopressinergic magnocellular neurons [6,7]. A minority of AVP gene variants causing adFNDI, such as the common G to A transition in position 55 of the coding DNA reference sequence (c.55G>A), also known as g.279G>A, according to previous nomenclature based on genomic location, are predicted to affect amino acid residues close to the SP cleavage site [8,9], resulting in abnormal post-translational processing and intracellular trafficking of preproAVP and proAVP [10]. Generally, these SP mutations cause a gradual decline in neurohypophyseal secretion of AVP during the first years of life, although wide variations in the age of onset and severity of symptoms have been reported [10], and are speculated to be consequences of environmental factors and individual abilities of scavenging the retained pathogenic aggregates of AVP precursors [6,11,12].…”