Forty-One Individuals With Mutations in the AVP-NPII Gene Associated With Familial Neurohypophyseal Diabetes Insipidus

García-Castaño, Alejandro; Madariaga, Leire; Nanclares, Gustavo Pérez de; Vela, Amaia; Rica, Itxaso; Gaztambide, Sonia; Martı́nez, Rosa; Piscina, Idoia Martinez de la; Urrutia, Inés; Aguayo, Aníbal; Velasco, Olaia; Eizaguirre, J.; Anton, Maria; Rodrı́guez, Alejandro; Rodríguez-Arnao, M. D.; Luzuriaga, Cristina; Villabona, C; Martinez, Francisco Eulógio; Carles, C.; Ramírez, Joaquín; Paz, F Nistal de; José, Francisco; Gómez, Pomares; Chueca, M.; Temboury, María del Carmen; Bahillo, María Pilar; Castaño, Luís

doi:10.1210/clinem/dgaa069

Cited by 9 publications

(9 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most of the variants of this gene are situated in the NPII gene, with seven variants detected [9]. As has been described, seven intrachain disulfide bonds are formed in NPII, which may be essential for stabilizing the protein.…”

Section: Discussionmentioning

confidence: 88%

“…First, there may be a decline in the number of binding sites and activity of endopeptidase responsible for the cleavage of ADH [8]. Second, there may be a change in the pattern of polymerization of NPII and its binding of ADH, which in turn may result in a specific enzymatic degradation of the hormone [9,10]. Both of these effects can lead to deficiency in the amount of available ADH.…”

mentioning

confidence: 99%

See 1 more Smart Citation

A case of central diabetes insipidus due to neurophysin II gene abnormality diagnosed based on a family history of nocturnal enuresis

et al. 2022

View full text Add to dashboard Cite

The etiology of central diabetes insipidus (DI) is classified into (1) idiopathic, (2) familial, and (3) secondary. Of these, familial central diabetes insipidus shows an autosomal dominant inheritance. We herein report a case in which this disease was diagnosed based on a family history of nocturnal enuresis. A 40-year-old man had had symptoms of polydipsia, polyuria and nocturia since childhood and found that his daughter had the same symptoms. Despite reaching nine years old, his daughter's nocturnal enuresis still had not improved, resulting in her consulting a pediatrician. She was suspected of having familial neurohypophyseal diabetes insipidus (FNDI) based on her family history and was referred along with her father for a detailed examination and treatment. A hypertonic saline load test (HSLT) to evaluate the arginine vasopressin (AVP) reaction was performed in both the proband and his daughter. The results showed no increase in AVP levels in response to high plasma osmolality. The water deprivation test (WDT) revealed he was suffering from partial DI. Based on the above findings and considering the possibility of familial central diabetes insipidus, we performed a gene mutation analysis of AVPneurophysin II (NPII). Both the father and daughter had an exon 2 abnormality in this gene (c232_234delGAG; pGlu78del), and this gene mutation is known to cause NPII protein abnormality, abolishing the function of AVP as a carrier protein. This case was considered to have provided an opportunity to understand the role of an NPII gene abnormality in familial central diabetes insipidus.

show abstract

Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

A case of central diabetes insipidus due to neurophysin II gene abnormality diagnosed based on a family history of nocturnal enuresis

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Previous studies have found a bioavailability of 10-20 times higher with the nasal administration than with the oral form [5,9,[14][15][16]. Based on previous practice, we decided to multiply the dose with 20 when converting nasal dose to oral dose, and multiply with 1.67 when converting sublingual dose to oral dose [3,7]. The "desmopressin dose requirement" was calculated as the sum of all desmopressin taken during one day after converting it to the equivalent oral doses.…”

Section: Primary Outcomementioning

confidence: 99%

“…The various etiologies of DI include congenital and acquired causes [1,2]. Most cases of cDI are acquired and may be due to neoplasm, infection, head trauma, hypophysitis, or surgery affecting the pituitary gland with the majority being due to neurosurgery, which may lead to both partial cDI and complete cDI [3,4].…”

Section: Introductionmentioning

confidence: 99%

Desmopressin Dose Requirements in Adults with Congenital and Acquired Central Diabetes Insipidus

Pedersen,

Andreassen,

Rasmussen

et al. 2023

Horm Metab Res

View full text Add to dashboard Cite

Central diabetes insipidus is a rare disorder characterized by a deficiency of vasopressin. The first line drug to treat this disorder is a synthetic analog of vasopressin, desmopressin.The primary aim of this retrospective register study was to compare desmopressin dose requirements in patients with acquired and congenital DI, and secondly to assess the influence of BMI on dose requirement and risk of hyponatremia with different drug administrations. We included all patients with suspected DI attending the endocrine department at Rigshospitalet, Copenhagen, Denmark in 2022. We identified 222 patients who were included whereof 130/222 (58.6 %) were female and median age was 53 years (IQR 35 to 63). The etiology included 7/222 (3.2 %) congenital and 215/222 (96.8 %) acquired. After converting nasal and sublingual doses to equivalent oral doses, the median daily dose requirement was 600 µg in patients with congenital etiology compared to 200 µg in patients with acquired etiology (p = 0.005). We found no association between BMI and desmopressin dose requirements (P=0.6). During the past 12 months, 66/215 (30.7%) had sodium levels < 136 mmol/L including 20/215 (9.3%) with sodium levels < 131 mmol/L. No increased risk of hyponatremia was found, when nasal and oral were compared (P=0.9). Daily desmopressin dose requirements were higher in patients with congenital DI compared to patients with acquired DI. However, this result was associated with uncertainty due to the small congenital group. BMI did not influence daily dose requirements and nor did type of administration influence the risk of hyponatremia.

show abstract

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

The autosomal dominant familial form of neurohypophyseal diabetes insipidus (adFNDI) is a rare inherited endocrine disorder characterized by hypotonic polyuria, severe thirst and polydipsia, which results from a deficient neurosecretion of the antidiuretic hormone, also known as arginine vasopressin (AVP). To date, adFNDI has been linked to more than 70 different heterozygous point mutations of the 2.5 kb AVP gene, encoding the composite precursor protein of AVP. A minority of disease-causing mutations, such as the common c.55G>A variant, are predicted to affect amino acid residues close to the signal peptide (SP) cleavage site, and result in abnormal post-translational processing and intracellular trafficking of AVP precursors exerting neurotoxic activity on vasopressinergic magnocellular neurons. Generally, SP variants cause a gradual decline in the neurohypophyseal secretion of AVP in small children, although a wide variability in clinical onset and severity of manifestations has been reported. For the first time, we describe a kindred from Calabria (Southern Italy) with adFNDI and document a partial clinical phenotype in one female young adult member of the family. Methods: A young adult woman was subjected to clinical, neuroradiological and genetic assessments for a mild, adolescent-onset, polyuric state at our Endocrinology Unit. Her family medical history revealed an early-onset (<12 years of age) occurrence of polyuria and polydipsia, which was successfully managed with high doses of oral desmopressin, and a typical adFNDI inheritance pattern that was seen over three generations. Results: In the index patient, the extensive hypertonic dehydration during fluid deprivation test elicited a prompt elevation of urine osmolality and diuresis contraction, indicative of a partial adFNDI phenotype. Diagnosis was confirmed by concordant hormonal tests and magnetic resonance imaging (MRI) evidence of a reduced hyperintense signal of the neurohypophysis, which was regarded as compatible with the depletion of the vasopressinergic magnocellular neurons. Direct DNA sequencing and restriction enzyme cleavage analysis revealed that a heterozygous c.55G>A transition, predicting a p.Ala19Thr replacement in the C-terminal region of SP, was the cause of adFNDI in the investigated kindred. Conclusions: The identification of the genetic cause of aFNDI in this Calabrian kindred provides further information and confirms the wide variability of disease onset and severity of manifestations related to SP variants of the AVP gene, supporting the need for genetic testing in all patients with familial occurrence of polyuria, regardless of their clinical and radiological phenotype. Even though sexual differences in the antidiuretic responses are documented, it is unclear whether female gender would attenuate clinical disease progression in the presence of a pathogenic c.55G>A mutation.

show abstract

Forty-One Individuals With Mutations in the AVP-NPII Gene Associated With Familial Neurohypophyseal Diabetes Insipidus

Cited by 9 publications

References 16 publications

A case of central diabetes insipidus due to neurophysin II gene abnormality diagnosed based on a family history of nocturnal enuresis

A case of central diabetes insipidus due to neurophysin II gene abnormality diagnosed based on a family history of nocturnal enuresis

Desmopressin Dose Requirements in Adults with Congenital and Acquired Central Diabetes Insipidus

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

Contact Info

Product

Resources

About