Molecular basis of autosomal dominant neurohypophyseal diabetes insipidus. Cellular toxicity caused by the accumulation of mutant vasopressin precursors within the endoplasmic reticulum.

Ito, Masafumi; Jameson, J. Larry

doi:10.1172/jci119357

Cited by 165 publications

(129 citation statements)

References 45 publications

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“…AVP is synthesized in the ER as the 145-amino acid prohormone proAVP and then is cleaved to the final AVP nonapeptide in post-Golgi compartments for release into the circulation via the posterior pituitary gland. The majority of congenital neurogenic (central) diabetes insipidus cases occur as an autosomal-dominant disease, whereby any one of dozens of mutations in the AVP gene (e.g., G57S or ΔE47) cause ER retention of proAVP and the formation of fibrillar aggregates (2,(5)(6)(7)(8). Recent studies have shown that activation of autophagy and autophagy-associated neuronal death occur in response to proAVP aggregation at later stages of diabetes insipidus in mouse models subjected to intermittent water deprivation (9); however, the molecular mechanisms underlying physiological and pathophysiological proAVP folding and degradation remain to be explored.…”

Section: Introductionmentioning

confidence: 99%

ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis

Shi¹,

Somlo²,

Kim³

et al. 2017

Journal of Clinical Investigation

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Section: Introductionmentioning

confidence: 99%

ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis

Shi¹,

Somlo²,

Kim³

et al. 2017

Journal of Clinical Investigation

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“…Expression studies have shown that dominant pro-vasopressin mutants are not secreted, but are retained in the endoplasmic reticulum (ER) (Beuret et al, 1999;Christensen et al, 2004;Friberg et al, 2004;Ito and Jameson, 1997;Nijenhuis et al, 1999;Olias et al, 1996;Siggaard et al, 1999). Most of the retained mutant protein is degraded by cytosolic proteasomes after retrotranslocation (Friberg et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Dominant pro-vasopressin mutants that cause diabetes insipidus form disulfide-linked fibrillar aggregates in the endoplasmic reticulum

Birk

Friberg

Prescianotto-Baschong

et al. 2009

Journal of Cell Science

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To assay for secretion, wild-type pro-vasopressin, the recessive mutant P7L, and the dominant mutants ⌬E47, Y2H, C28Y and ⌬G227 were expressed in COS-1 cells, pulse-labeled with [ 35 S]methionine/cysteine, chased for 2 hours, isolated from the cells and from the media by immunoprecipitation, and analyzed by SDSgel electrophoresis and autoradiography ( Fig. 2A). As expected, a considerable fraction of the wild type and of P7L was recovered from the media, reflecting their ability to fold and pass ER quality control. By contrast, the dominant mutants ⌬E47, Y2H and C28YAutosomal dominant neurohypophyseal diabetes insipidus results from mutations in the precursor protein of the antidiuretic hormone arginine vasopressin. Mutant prohormone is retained in the endoplasmic reticulum of vasopressinergic neurons and causes their progressive degeneration by an unknown mechanism. Here, we show that several dominant provasopressin mutants form disulfide-linked homo-oligomers and develop large aggregations visible by immunofluorescence and immunogold electron microscopy, both in a fibroblast and a neuronal cell line. Double-labeling showed the pro-vasopressin aggregates to colocalize with the chaperone calreticulin, indicating that they originated from the endoplasmic reticulum.The aggregates revealed a remarkable fibrillar substructure. Bacterially expressed and purified mutant pro-vasopressin spontaneously formed fibrils under oxidizing conditions. Mutagenesis experiments showed that the presence of cysteines, but no specific single cysteine, is essential for disulfide oligomerization and aggregation in vivo. Our findings assign autosomal dominant diabetes insipidus to the group of neurodegenerative diseases associated with the formation of fibrillar protein aggregates.

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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: Introductionmentioning

confidence: 76%

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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Molecular basis of autosomal dominant neurohypophyseal diabetes insipidus. Cellular toxicity caused by the accumulation of mutant vasopressin precursors within the endoplasmic reticulum.

Cited by 165 publications

References 45 publications

ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis

ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis

Dominant pro-vasopressin mutants that cause diabetes insipidus form disulfide-linked fibrillar aggregates in the endoplasmic reticulum

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

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