Mutations in the Vasopressin Prohormone Involved in Diabetes Insipidus Impair Endoplasmic Reticulum Export but Not Sorting

Nijenhuis, Marga; Zalm, R.; Burbach, J. Peter H.

doi:10.1074/jbc.274.30.21200

Cited by 55 publications

(67 citation statements)

References 43 publications

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“…Expression of a number of I neurohypophysial DI constructs in cultured cells showed that all resulted in retention of mutant vasopressin prohormone in the endoplasmic reticulum (Siggaard et ul. 1999;Nijenhuis et al 1999), with structural disruption of the endoplasmic reticulum when neuro2a cells were used (Nijenhuis et al 1999). These findings support the hypothesis that a defect in intracellular transport is the underlying defect in familial neurohypophysial DI, and that prior neuronal death is not required for development of the diabetes insipidus phenotype.…”

Section: F D Grantsupporting

confidence: 76%

Genetic models of vasopressin deficiency

Grant

2000

Experimental Physiology

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Animal models of genetic hormone deficiency are useful as models for physiological studies of hormone deficiency and hormone action. Structure—function studies of the specific underlying gene defect may help in understanding mechanisms regulating gene expression and secretion of the peptide product. Spontaneous genetic models of vasopressin deficiency, such as the Brattleboro rat and human familial diabetes insipidus, have facilitated many studies of vasopressin. However, the Brattleboro rat may not be an ideal model of genetic vasopressin deficiency and therefore could be less useful for studies of the central nervous system or as a background strain for the introduction of new vasopressin gene constructs. The human model is appropriately limited by the constraints of human studies, so that engineered animal models of specific diseases, such as familial neurohypophysial diabetes insipidus, are required. The recent development of a vasopressin‐null mouse may provide insights into the various roles of vasopressin in the stress response, cardiovascular regulation and behaviour. Additionally, animals with a complete genetic deficiency of vasopressin can serve as a background strain for introduction of novel vasopressin gene constructs to enable sophisticated studies of the regulation of vasopressin expression and the intracellular processes required for appropriate secretion of vasopressin peptide. As advanced techniques of genetic manipulation become more reliable, conditional expression of vasopressin, regulated by time or body site will permit even more detailed studies in this field.

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Section: F D Grantsupporting

confidence: 76%

Genetic models of vasopressin deficiency

Grant

2000

Experimental Physiology

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“…Mutations affecting the AVP-NPII gene are predicted to determine cytotoxic accumulation of the prohormone in the supraoptic and paraventricular nuclei, ultimately leading to neuronal damage. The expression of mutations causing adFNDI in cell models supports this hypothesis, because the mutant AVP prohormone was constantly found to be retained in the endoplasmic reticulum (11)(12)(13)(14)(15)(16)(17). More recently, these observations have been confirmed in transgenic animals expressing a mutated AVP-NPII gene (18 -20).…”

Section: Introductionsupporting

confidence: 67%

Identification of a novel mutation in the arginine vasopressin-neurophysin II gene affecting the sixth intrachain disulfide bridge of the neurophysin II moiety

Baglioni

Corona

Maggi

et al. 2004

European Journal of Endocrinology

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Objective: Most mutations of the arginine vasopressin-neurophysin II (AVP-NPII) gene cause autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI). Such mutations are predicted to alter the three-dimensional structure of the prohormone, which accumulates in the cell body, ultimately leading to neuronal degeneration and hormonal deficit. In this study we describe the case of a 26-year-old female reporting a long-lasting history of polyuria/polydipsia. The father of the patient was affected by diabetes insipidus and was under desmopressin treatment until the time of his death. Nevertheless, the patient had never been subjected to endocrine evaluation. Design and methods: Clinical and genetic studies were performed. An 8-h fluid deprivation test plus desmopressin challenge and a 5% saline solution test were performed, in order to confirm the diagnosis. DNA was extracted from peripheral blood lymphocytes and subjected to direct sequencing of the entire coding region of the AVP-NPII gene. Results and conclusions: Clinical assessment of the patient confirmed the diagnosis of neurohypophyseal diabetes insipidus. Desmopressin treatment was started, which effectively reversed the polyuria/ polydipsia syndrome. Genetic analysis revealed a novel mutation (1665T . A) in exon 2 of the AVP-NPII gene, disrupting one of the disulfide bonds present in the NPII moiety which play a fundamental role in determining the proper folding of the molecule. In summary, in the present study we have described a novel mutation of the AVP-NPII gene, which is consistent with the malfolding/toxicity hypothesis underlying the pathogenesis of adFNDI.European Journal of Endocrinology 151 605-611

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“…performed functional analyses of fi ve mutations in the AVP gene, three of them in glycine residues (G45R, G96V and G88S, respectively NP14G, NP65G and NP57G positions on neurophysin). The analyzes of mutation G88S displayed a relatively effi cient processing and secretion of protein, an aberrant distribution of the mutant prohormone within the endoplasmic reticulum (ER) and a modifi cation in ER distribution in cells (13). Therefore, they propose that the accretion and the consequent disturbance of the ER are deleterious to the cell and will decrease the functionality and/or the viability of the magnocellular neurons, which express high amounts of vasopressin prohormone in vivo (13).…”

Section: Familial Diabetes Insipidus Due To Avp Mutationmentioning

confidence: 99%

“…The analyzes of mutation G88S displayed a relatively effi cient processing and secretion of protein, an aberrant distribution of the mutant prohormone within the endoplasmic reticulum (ER) and a modifi cation in ER distribution in cells (13). Therefore, they propose that the accretion and the consequent disturbance of the ER are deleterious to the cell and will decrease the functionality and/or the viability of the magnocellular neurons, which express high amounts of vasopressin prohormone in vivo (13). This hypothesis would explain both the dominant inheritance of human adFN-DI and the delayed onset of the symptoms, as observed in some patients here described.…”

Section: Familial Diabetes Insipidus Due To Avp Mutationmentioning

confidence: 99%

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

Melo

Marui

Brito

et al. 2008

Arq Bras Endocrinol Metab

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Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a rare autosomal dominant disorder characterized by polyuria and polydipsia due to defi ciency 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 amplifi cation 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.

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Mutations in the Vasopressin Prohormone Involved in Diabetes Insipidus Impair Endoplasmic Reticulum Export but Not Sorting

Cited by 55 publications

References 43 publications

Genetic models of vasopressin deficiency

Genetic models of vasopressin deficiency

Identification of a novel mutation in the arginine vasopressin-neurophysin II gene affecting the sixth intrachain disulfide bridge of the neurophysin II moiety

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

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