Familial Neurohypophyseal Diabetes Insipidus Research Articles

PS-039 A New Mutation Causing Familial Neurohypophyseal Diabetes Insipidus In A Portuguese Family

<h3>Background and aim</h3> Familial Neurohypophyseal Diabetes Insipidus (FNDI) is a rare autossomal dominant disorder caused by mutations in the vasopressin (AVP) gene and is characterised by childhood onset of polyuria and polydipsia. The authors present a case of FNDI caused by a new mutation in AVP gene in a Portuguese family. <h3>Case Report</h3> Twelve year-old boy with unremarkable past medical history admitted at our outpatient clinic with complaints of polydipsia (20 Litres/day) and polyuria since early childhood. Polyphagia, weight loss, enuresis and urinary incontinence were denied. His mother, grandmother, great grandfather and second/third degree uncles/aunts presented the same symptoms. Basal laboratorial tests revealed: plasma osmolality 292 mOsm/KgH₂O, plasma Na + 137 mEq/L and a normal renal function. 24-hour urinalysis (volume 7450 mL) showed a low urine osmolality (150 mOsm/KgH₂O) and normal Na+ and creatinine concentrations. Water deprivation test was positive for Diabetes Insipidus. The positive response after 20 mcg of intranasal desmopressin confirmed the diagnosis of neurohypophyseal Diabetes Insipidus. The MRI showed a hyper-intense signal corresponding to an ectopic neurohypophysis in the supra-celar cistern. The genetic test confirmed the diagnosis of FNDI: mutation c.293G &gt; C (p. Cys98Ser) in the AVP gene (heterozygous) in the proband, mother and grandmother. The patient started daily oral desmopressin with relieve of complaints. Genetic counselling was given to the family. <h3>Conclusion</h3> The presented case revealed an AVP gene mutation not described in the literature. The diagnosis, not recognised until the fourth generation, allowed a prompt treatment and genetic counselling of the family and an improvement in quality of life of affected members.

Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a mutation in the arginine-vasopressin II gene in four generations of a Korean family.

Autosomal dominant neurohypophyseal diabetes insipidus is a rare form of central diabetes insipidus that is caused by mutations in the vasopressin-neurophysin II (AVP-NPII) gene. It is characterized by persistent polydipsia and polyuria induced by deficient or absent secretion of arginine vasopressin (AVP). Here we report a case of familial neurohypophyseal diabetes insipidus in four generations of a Korean family, caused by heterozygous missense mutation in exon 2 of the AVP-NPII gene (c.286G>T). This is the first report of such a case in Korea.

Dilatative Uropathy as a Manifestation of Neurohypophyseal Diabetes Insipidus due to a Novel Mutation in the Arginine Vasopressin-Neurophysin-II Gene

Polydypsia and polyuria are frequent symptoms in patients with sellar masses caused by neurohypophyseal diabetes insipidus. Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI), a disorder caused by mutations in the arginine vasopressin (AVP) -neurophysin II (NPII) gene, should be considered as a rare differential diagnosis. A delayed diagnosis bears the risk of life-threatening electrolyte imbalances and permanent urinary tract damage, leading to impaired quality of life.We present a Caucasian kindred of at least 4 generations with FNDI.Clinical histories, endocrine para-meters, and results of molecular analyses of the AVP gene are presented with a review of the literature on diabetes insipidus (DI) related urinary tract dilatation.Polyuria and polydipsia were only reported based on explicit and thorough interrogation after more than 4 years of clinical follow-up. A novel heterozygous mutation in the AVP gene was found in all examined symptomatic subjects (c.1-33_c.4del37nt). A literature review revealed that non-obstructive hydronephrosis (NOH) is a rare but known complication of DI.Since increased fluid intake is often a typical familial pattern in adFNDI, it is frequently missed as being pathologic in affected patients, therefore a detailed clinical history of drinking volumes is of critical importance. AVP gene testing is an important component in the confirmation of the diagnosis. Otherwise unexplainable NOH should lead to further investigations and evaluation of rare diseases like FNDI.

A missense mutation in the arginine‐vasopressin neurophysin‐II gene causes autosomal dominant neurohypophyseal diabetes insipidus in a Chinese family

Familial neurohypophyseal diabetes insipidus, an autosomal dominant disorder, is mostly caused by mutations in the genes that encode AVP or its intracellular binding protein, neurophysin-II. The mutations lead to aberrant preprohormone processing and progressive destruction of AVP-secreting cells, which gradually manifests a progressive polyuria and polydipsia during early childhood, and a disorder of water homeostasis. We characterized the clinical and biochemical features, and sequenced the AVP neurophysin-II(AVP-NPII) gene of the affected individuals with autosomal dominant neurohypophyseal diabetes insipidus(ADNDI)to determine whether this disease was genetically determined. We obtained the histories of eight affected and four unaffected family individuals. The diagnosis of ADNDI was established using a water deprivation test and exogenous AVP administration. For molecular analysis, genomic DNA was extracted and the AVP-NPII gene was amplified using polymerase chain reaction and sequenced. The eight affected individuals showed different spectra of age of onsets (7-15 years) and urine volumes (132-253 ml/kg/24 h). All affected individuals responded to vasopressin administration, with a resolution of symptoms and an increase in urine osmolality by more than 50%. The characteristic hyperintense signal in the posterior pituitary on T1-weighted magnetic resonance imaging was absent in six family members and present in one. Sequencing analysis revealed a missense heterozygous mutation 1516G > T (Gly17Val) in exon 2 of the AVP-NPII gene among the ADNDI individuals. We identified a missense mutation in the AVP-NPII gene and the same mutation showed different spectra of age of onsets and urine volumes in a new Chinese family with ADNDI. The mutation may provide a molecular basis for understanding the characteristics of NPII and add to our knowledge of the pathogenesis of ADNDI, which would allow the presymptomatic diagnosis of asymptomatic subjects.

A novel deletion partly removing the AVP gene causes autosomal recessive inheritance of early‐onset neurohypophyseal diabetes insipidus

Familial neurohypophyseal diabetes insipidus (FNDI) typically presents with age-dependent penetrance and autosomal dominant inheritance caused by missense variations in one allele of the AVP gene encoding the arginine vasopressin (AVP) prohormone. We present the molecular genetic characteristics underlying an unusual form of FNDI occurring with very early onset and seemingly autosomal recessive inheritance. By DNA amplification and sequencing, we identified a novel variant allele of the AVP gene carrying a 10,396 base pair deletion involving the majority of the AVP gene as well as its regulatory sequences in the intergenic region between the AVP and the OXT gene, encoding the oxytocin prohormone. We found two chromosomes carrying the deletion in affected family members and one in unaffected family members suspected to transmit the deleted allele. Whole-genome array analysis confirmed the results and excluded the presence of any additional major pathogenic abnormalities. The deletion is predicted to abolish the transcription of the AVP gene, thus the fact that family members heterozygous for the deletion remain healthy argues, in general, against haploinsufficiency as the pathogenic mechanism FNDI. Accordingly, our data is strong support to the prevailing idea that dominant inheritance of FNDI is due to a dominant-negative effect exerted by variant AVP prohormone.

Late‐onset familial neurohypophyseal diabetes insipidus due to a novel mutation in the AVP gene

Familial neurohypophyseal diabetes insipidus (FNDI) is mainly an autosomal dominant inherited disorder presenting with severe polydipsia and polyuria in early childhood. In this study, we aimed to determine the molecular genetics and clinical characteristics of a large Swedish-Norwegian family presenting with very late-onset autosomal dominant FNDI. Six probands with a history of developing polyuria and polydipsia during adolescence were studied. Information on family demography was collected by personal interview with family members. The genetic cause of FNDI was identified by DNA sequencing analysis of the coding regions of the AVP gene. The clinical characteristics were determined by the measurement of basal urine production and osmolality as well as by measurements of concurrent levels of plasma AVP, plasma osmolality, and urine osmolality during fluid deprivation and bolus injection of DDAVP. The integrity of the neurohypophysis was evaluated by magnetic resonance imaging. The mean age of encountering the first clinical symptoms in the family was 14·8 years (range 3-30 years) (n = 17). All six affected subjects investigated were heterozygous for a novel mutation in the AVP gene (g.1848C>T) predicting a p.Pro84Leu substitution in the AVP precursor protein. We found partial deficiency in evoked AVP secretion during fluid deprivation in one subject and complete deficiency in another. The pituitary bright spot was absent in all six affected subjects studied. A novel mutation in the AVP gene predicted to cause a neurophysin II dimerization defect is causing surprisingly late onset of FNDI in a large, six generation, Swedish-Norwegian family. The mutation is associated with both complete and partial deficiency in evoked AVP secretion during fluid deprivation in patients who have suffered from FNDI for decades.

A novel variation in the AVP gene resulting in familial neurohypophyseal diabetes insipidus in a large Italian kindred

Familial neurohypophyseal diabetes insipidus (FNDI) is mostly an autosomal dominant inherited disorder presenting with severe polydipsia and polyuria typically in early childhood. To date, 69 different variations in the AVP gene encoding the AVP prohormone have been identified in autosomal dominant FNDI (adFNDI). In this study we present a family of seven generations, in which a novel variation in the AVP gene seems to cause adFNDI. Clinical assessment by 24h urine collection, water deprivation test, desmopressin (dDAVP) challenge, and magnetic resonance imaging (MRI) of the posterior pituitary are presented. The diagnosis of adFNDI was confirmed by direct DNA sequence analysis of the AVP gene. Inheritance pattern and clinical history clearly pointed towards adFNDI. Inability of concentrating urine upon dehydration was demonstrated by a water deprivation test, and neurohypophyseal diabetes insipidus was strongly suspected after dDAVP administration, during which renal concentration ability quadrupled. MRI revealed a very weak pituitary "bright spot" in each of six subjects and a further reduction in the size of the neurohypophysis in a 7-year follow-up MRI scan in one subject. DNA sequence analysis revealed heterozygousity for a novel g.1785T>C gene variation predicting a p.Leu63Pro substitution in four affected subjects. Genetic testing in the diagnostic evaluation of families in which diabetes insipidus segregates is highly recommended in that interpretation of clinical assessments can be difficult. Furthermore, presymptomatic diagnosis can ease the parental concern of the carrier status of their offspring, and also avoid unnecessary surveillance of those being unaffected.

Clinical and molecular analysis of a Chinese family with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel missense mutation in the vasopressin–neurophysin II gene

The objective of this study is to identify the genetic defects in a Chinese family with autosomal dominant familial neurohypophyseal diabetes insipidus. Complete physical examination, fluid deprivation, and DDAVP tests were performed in three affected and three healthy members of the family. Genomic DNA was extracted from leukocytes of venous blood of these individuals for polymerase chain reaction amplification and direct sequencing of all three coding exons of arginine vasopressin-neurophysin II (AVP-NPII) gene. Seven members of this family were suspected to have symptomatic vasopressin-deficient diabetes insipidus. The water deprivation test in all the patients confirmed the diagnosis of vasopressin-deficient diabetes insipidus, with the pedigree demonstrating an autosomal dominant inheritance. Direct sequence analysis revealed a novel mutation (c.193T>A) and a synonymous mutation (c.192C>A) in the AVP-NPII gene. The missense mutation resulted in the substitution of cysteine by serine at a highly conserved codon 65 of exon 2 of the AVP-NPII gene in all affected individuals, but not in unaffected members. We concluded that a novel missense mutation in the AVP-NPII gene caused neurohypophyseal diabetes insipidus in this family, due to impaired neurophysin function as a carrier protein for AVP. The Cys65 is essential for NPII in the formation of a salt bridge with AVP. Presence of this mutation suggests that the portion of the neurophysin peptide encoded by this sequence is important for the normal expression of vasopressin.

Familial neurohypophyseal diabetes insipidus due to a novel mutation in the arginine vasopressin–neurophysin II gene

Familial neurohypophyseal (central) diabetes insipidus (DI) is caused by mutations in the arginine vasopressin-neurophysin II (AVP-NPII) gene. The majority of cases is inherited in an autosomal dominant way. In this study, we present the clinical features of a mother and her son with autosomal dominant neurohypophyseal DI caused by a novel mutation. A thirty-four-year-old woman and her three-year-old son were evaluated because of polyuria and polydipsia since the age of 1.5 years onwards. Both patients were subjected to a water deprivation test confirming the diagnosis of central DI. Magnetic resonance imaging of the brain of the mother showed a hypothalamus without apparent abnormalities and a relatively small neurohypophysis without a hyperintense signal. Mutation analysis showed a c.322G>T (p.?/p.Glu108X) in Exon 2 of the AVP-NPII gene in both mother and son. This study reports neurohypophyseal DI in a mother and her son due to a novel mutation in Exon 2 of the AVP-NPII gene. Clinical and pathophysiological aspects of this disease are shortly reviewed and discussed.

Misfolding of Mutated Vasopressin Causes ER-Retention and Activation of ER-Stress Markers in Neuro-2a Cells

SummaryArginine-vasopressin (AVP) is a peptide hormone normally secreted from neuroendocrine cells via the regulated secretory pathway. In Familial Neurohypophyseal Diabetes Insipidus (FNDI), an autosomal dominant form of central diabetes insipidus, mutations of pro-vasopressin appear to accumulate in the endoplasmic reticulum (ER) causing a lack of biologically active AVP in the blood. To investigate the effect of pro-vasopressin mutations regarding intracellular functions of protein targeting and secretion, we created two FNDI-associated amino acid substitution mutants, e.g., G14R, and G17V in frame with green fluorescent protein (GFP) and pro-vasopressin (VP) in frame with red fluorescent protein (VP-RFP). Fluorescence microscopy of Neuro-2a cells expressing these constructs revealed co-localization of VP-GFP and VP-RFP to punctate granules along the length and accumulating at the tips of neurites, characteristic of regulated secretory granules. In contrast, the two FNDI-associated amino acid substitution mutants, e.g., G14R-GFP, and G17VGFP, were localized to a perinuclear region of the Neuro-2a cells characteristic of the endoplasmic reticulum. Co-expression of these mutants with VP-RFP showed VP-RFP was retained in the ER, co-localized with the mutants suggesting the formation of heterodimers as found in FNDI. Stimulated secretion experiments indicated that VP-GFP was secreted in an inducible manner whereas, G14R-GFP and G17V-GFP were retained to nearly 100% within the cells. Analysis by western blotting and semi-quantitative RT-PCR indicated an increased protein and mRNA expression for an ER resident molecular chaperone, BiP. Further analysis of ER-storage disease-associated proteins such as caspase 12 and CHOP showed an increase in these as well. The results suggest that G14R-GFP and G17V-GFP are retained in the ER of Neuro-2a cells, resulting in up-regulation of the molecular chaperone BiP, and activation of the ER-storage disease-associated caspase cascade system.

Growth retardation in untreated autosomal dominant familial neurohypophyseal diabetes insipidus caused by one recurring and two novel mutations in the vasopressin-neurophysin II gene

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI), a disorder caused by mutations in the vasopressin (AVP)-neurophysin II (NPII) gene, manifests gradually during early childhood with progressive polyuria and polydipsia. Patients are usually treated with synthetic AVP analog. If unlimited access to water is provided, prognosis is usually good even in the absence of specific treatment. In this study, we describe three families with adFNDI, in which growth failure was a prominent complaint, on the clinical and molecular level. Histories from affected and unaffected family members were taken. Height and weight of index patients were recorded longitudinally. Patients underwent water deprivation tests, magnetic resonance imaging, and genetic analysis. One mutant was studied by heterologous expression in cell culture. A total of ten affected individuals were studied. In two of the three pedigrees, a novel mutation in the AVP-NPII gene was found. The index children in each pedigree showed growth retardation, which was the reason for referral in two. In these cases, water intake was tightly restricted by the parents in an attempt to overcome suspected psychogenic polydipsia and to improve appetite. Once the children were treated by hormone replacement, they rapidly caught up to normal weight and height. Genetic testing and appropriate parent counseling should be enforced in adFNDI families to ensure adequate treatment and avoid chronic water deprivation, which causes failure to thrive.

Polyuria and polydipsia in a young child: diagnostic considerations and identification of novel mutation causing familial neurohypophyseal diabetes insipidus

A 3-year 5-month-old boy was seen for second opinion regarding polydipsia and polyuria. Previously, a diagnosis of primary polydipsia was made after normal urine concentration after overnight water deprivation testing. The boy's father, paternal grandfather, and paternal aunt had diabetes insipidus treated with desmopressin acetate. Based on this young boy's symptoms, ability to concentrate urine after informal overnight water deprivation, and family history of diabetes insipidus, we performed AVP gene mutation testing. Analysis of the AVP gene revealed a novel mutation G54E that changes a normal glycine to glutamic acid, caused by a guanine to adenine change at nucleotide g.1537 (exon 2) of the AVP gene. Commonly, patients with familial neurohypophyseal diabetes insipidus (FNHDI) present within the first 6 years of life with progressively worsening polyuria and compensatory polydipsia. Since these patients have progressive loss of arginine vasopressin (AVP), they may initially respond normally to water deprivation testing and have normal pituitary findings on brain MRI. Genetic testing may be helpful in these patients, as well as preemptively diagnosing those with a mutation, thereby avoiding unnecessary surveillance of those unaffected.

Autosomal Dominant Neurohypophyseal Diabetes Insipidus in Two Families

Background: Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a rare disease with symptoms of polydipsia, polyuria and dehydration caused by arginine vasopressin deficiency. Disease onset is within infancy or adolescence. A variety of disease-causing mutations of the arginine vasopressin neurophysin II gene (AVP) on chromosome 20p13 have been described. Methods: Two Polish families with adFNDI were screened for mutations. Processing of wild-type (WT) and mutant AVP was monitored using immunocytochemical methods in stably transfected Neuro2A cells. AVP secretion into the cell culture supernatant was investigated with an enzyme immunoassay. Results: In the first family a heterozygous p.G96D mutation was identified. Some patients additionally carried a novel heterozygous mutation p.A159T. The second family presented with a heterozygous mutation p.C98G. Confocal laser microscopy unveiled accumulation of p.G96D and p.C98G prohormones in the cellular bodies, whereas WT and p.A159T prohormones and/or processed products were located in the tips of cellular processes. Reduced levels of AVP in supernatant culture medium of p.G96D and p.C98G transfected cells in comparison to p.A159T and WT cells were found. Conclusions: We conclude that the p.G96D and p.C98G mutations cause adFNDI in the two reported families. The sequence variant p.A159T does not seem to have disease-causing effects.

Utility of AVP gene testing in familial neurohypophyseal diabetes insipidus

Familial neurohypophyseal diabetes insipidus (FNDI) is a rare disorder resulting from arginine vasopressin (AVP) gene mutations. A partial defect in AVP secretion occurs early in the course of FNDI and may not be detected by a water deprivation test (WDT). Testing for AVP gene mutations may confirm a diagnosis of FNDI when a WDT is inconclusive and may also predict individuals who will later develop FNDI. To test the utility of AVP gene analysis in confirming the diagnosis of FNDI. Five families (20 subjects, 14 symptomatic and six asymptomatic) with FNDI and nine children with idiopathic neurohypophyseal diabetes insipidus (INDI). Genomic DNA was analysed for AVP gene mutations using polymerase chain reaction (PCR) amplification and sequencing. Heterozygous AVP gene mutations were found in all subjects with FNDI but none of the ICDI patients. Each family had their own distinct mutation. We identified two novel mutations (C44W and C105S). One asymptomatic subject developed diabetes insipidus (DI) 4 months after detection of an AVP gene mutation. The WDT suggested partial DI in 4/6 but was normal in 2/6 children with FNDI. AVP gene testing allowed diagnostic confirmation of FNDI when the WDT was inconclusive in symptomatic children, therefore obviating the need for a repeat WDT and enabling earlier initiation of appropriate treatment. AVP gene testing also has the potential to identify which asymptomatic children will later develop FNDI.

Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a novel mutation in arginine-vasopressin gene in a Brazilian family

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a rare autosomal dominant disorder characterized by polyuria and polydipsia due to deficiency of arginine vasopressin (AVP). More than 50 mutations causing adFNDI have been already reported in the AVP gene. The aim of the present study is to analyze the AVP gene in four generations of one Brazilian kindred with adFNDI. The proband was a 31-year old female with huge hypotonic polyuria (10 L/day) dated from childhood. Molecular analysis included amplification of all exons and exon-intron regions of the AVP gene by PCR and direct sequencing. Sequencing analysis showed a novel point mutation in heterozygous: G88V (GGC>GTC). All affected patients presented the same mutation also in heterozygous, while it was absent in four normal members. We expand the repertoire of mutations in AVP describing the novel G88V mutation in one Brazilian kindred with adFNDI.

Akt Induces Apoptosis in Neuroblastoma Cells Expressing a C98X Vasopressin Mutant Following Autophagy Suppression

Mutations in the arginine vasopressin (AVP)-neurophysin II (NP-II) gene that affect the folding and transport of the prohormone result in loss of secretion of the anti-diuretic hormone AVP from pituitary nerve terminals and cause autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI). One such mutation consists of the replacement of a Cys residue at position 98 with a stop codon (C98X) in the AVP precursor (corresponding to C67X in NP domain). In neuroblastoma cells over-expressing this truncated AVP precursor autophagy, a macromolecular degradation process, was shown to be essential for assuring cell survival. In the present study, we investigated the role of the Akt pro-survival signalling in the regulation of autophagy and of apoptosis linked with the handling of C98X AVP. Impairing autophagy-lysosomal sequestration or cathepsin D (CD)-mediated proteolysis triggered the activation of the intrinsic death pathway of apoptosis in C98X-expressing cells, but not in the wild-type -AVP-expressing cells. This was shown by the expression of a Vps34 dominant negative, which down-regulates the PI3k class III-dependent signalling needed for autophagosome (APH) formation, by genetic silencing as a result of RNA interference (RNAi) of Lamp2, a protein indispensable for the fusion of APHs with lysosomes, and by RNAi silencing of the lysosomal protease CD. Ectopic expression of either the wild-type or the mutated C98X AVP altered neither the expression nor the phosphorylation of the pro-survival signalling molecule Akt. Strikingly, the ectopic adenoviral-directed expression of a constitutively active Akt, instead of preserving cell survival, resulted in the suppression of autophagy, and precipitated Bax-mediated cell death. The present data demonstrate the need for autophagy-mediated degradation of mutated C98X peptides, which otherwise become toxic to the cell, and suggest that, in the presence of mis-folded proteins, the stimulation of the Akt signalling counteracts the beneficial effects of autophagy and precipitates cell death. It follows that growth factors impinging on the Akt pathway may have deleterious effect in neurones expressing mutant neuropeptides. This can provide an explanation for the late onset and progressive neuronal cell loss observed in hypothalamic magnocellular neurones of adFNDI patients.

A Novel Mutation of the Vasopressin-Neurophysin II Gene in a Familial Neurohypophyseal Diabetes Insipidus

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a rare form of central diabetes insipidus (DI), and this malady is clinically characterized by polydipsia and polyuria, and it is caused by mutation in the vasopressin-neurophysin II. We identified a Korean family that suffered with adFNDI and we found a novel mutation in the NP II molecule. The index subject’s DI symptoms dated to childhood, and his familial history was consistent with autosomal transmission. The diagnosis of central DI was done by performing a water deprivation test and a vasopressin challenge test. For molecular analysis, the genomic DNA was ext racted and the AVP-NP II gene was amplified by polymerase chain reaction from four clinically-affected members and seven clinically-nonaffected members. Genetic analysis of AVP-NP II revealed new a heterozygous missense mutation in exon 2 of the AVP-NP II gene (+1692C > A) and this amino acid substitution (Cys105Stop) was predicted to have occurred in four clinically-affected subjects. In summary, in the present study we have described a novel mutation of the AVP-NPII gene in a Korean family suffering with adFNDI. (J Kor Endocrine Soc 22:118~124, 2007)

Protein Misfolding and Human Disease

Protein misfolding is a common event in living cells. In young and healthy cells, the misfolded protein load is disposed of by protein quality control (PQC) systems. In aging cells and in cells from certain individuals with genetic diseases, the load may overwhelm the PQC capacity, resulting in accumulation of misfolded proteins. Dependent on the properties of the protein and the efficiency of the PQC systems, the accumulated protein may be degraded or assembled into toxic oligomers and aggregates. To illustrate this concept, we discuss a number of very different protein misfolding diseases including phenylketonuria, Parkinson's disease, alpha-1-antitrypsin deficiency, familial neurohypophyseal diabetes insipidus, and short-chain acyl-CoA dehydrogenase deficiency. Despite the differences, an emerging paradigm suggests that the cellular effects of protein misfolding provide a common framework that may contribute to the elucidation of the cell pathology and guide intervention and treatment strategies of many genetic and age-dependent diseases.

Familial Neurohypophyseal Diabetes Insipidus—An Update

Although molecular research has contributed significantly to our knowledge of familial neurohypophyseal diabetes insipidus (FNDI) for more than a decade, the genetic background and the pathogenesis still is not understood fully. Here we provide a review of the genetic basis of FNDI, present recent progress in the understanding of the molecular mechanisms underlying its development, and survey diagnostic and treatment aspects. FNDI is, in 87 of 89 kindreds known, caused by mutations in the arginine vasopressin (AVP) gene, the pattern of which seems to be largely revealed as only few novel mutations have been identified in recent years. The mutation pattern, together with evidence from clinical, cellular, and animal studies, points toward a pathogenic cascade of events, initiated by protein misfolding, involving intracellular protein accumulation, and ending with degeneration of the AVP producing magnocellular neurons. Molecular research has also provided an important tool in the occasionally difficult differential diagnosis of DI and the opportunity to perform presymptomatic diagnosis. Although FNDI is treated readily with exogenous administration of deamino-D-arginine vasopressin (dDAVP), other treatment options such as gene therapy and enhancement of the endoplasmic reticulum protein quality control could become future treatment modalities.

A novel heterozygous missense mutation in the vasopressin moiety is identified in a Japanese person with neurohypophyseal diabetes insipidus

The autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is caused by diverse mutations in one allele of the gene that encodes the arginine vasopressin (AVP) precursor protein, AVP-neurophysin II (AVP-NP II). Most of the mutations identified so far are located in either the signal peptide or NP II moiety. Two recently published mutations in the AVP gene identified in kindreds with adFNDI predict a substitution of histidine for tyrosine at position 2 and a deletion of phenylalanine at position 3 in AVP. They are unique among adFNDI mutations in that they are the only adFNDI mutations that affect amino acid residues in the AVP moiety of the pro-hormone. Here, we report a novel heterozygous missense mutation in the AVP moiety of the AVP-NP II gene in a Japanese person with neurohypophyseal diabetes insipidus (DI). This mutation occurs at position 2 in AVP and predicts a substitution of serine for tyrosine (Y21S). It is expected to interfere with normal binding of AVP with NP II, and thus result in misfolding of the precursor proteins. The data of this study support the notion that mutations affecting the AVP moiety can result in the initiation of the pathological processes.