A murine model of autosomal dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-producing neurons

Russell, Theron A.; Ito, Masafumi; Ito, Mika; Yu, Richard N.; Martinson, Fred A.; Weiss, Jeffrey P.; Jameson, J. Larry

doi:10.1172/jci18616

Cited by 45 publications

(56 citation statements)

References 57 publications

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“…All the reported mutations are expected to replace or eliminate one or more amino acids known, or reasonably assumed, to be critical for a proper processing, dimerization, disulfide bond formation, and folding of the vasopressin precursor in the endoplasmic reticulum (ER) (3). In autosomal dominant CDI, abnormal processing of vasopressin precursors in the supraoptic and paraventricular nuclei, and mutant AVP precursors impair intracellular trafficking of the WT precursor from the ER to the Golgi apparatus by forming heterodimers, with a reduction in the bioavailability of active AVP (14,15,16). The pathophysiological loss of PPI at MRI in our patients can also be explained by the abnormal processing of vasopressin precursors in the hypothalamic nuclei leading to the impairment of intracellular trafficking with a similar mechanism (2,14,15,16).…”

Section: Discussionmentioning

confidence: 66%

“…In autosomal dominant CDI, abnormal processing of vasopressin precursors in the supraoptic and paraventricular nuclei, and mutant AVP precursors impair intracellular trafficking of the WT precursor from the ER to the Golgi apparatus by forming heterodimers, with a reduction in the bioavailability of active AVP (14,15,16). The pathophysiological loss of PPI at MRI in our patients can also be explained by the abnormal processing of vasopressin precursors in the hypothalamic nuclei leading to the impairment of intracellular trafficking with a similar mechanism (2,14,15,16). In our two patients, the signs and symptoms of CDI became evident by the age of 4 years, suggesting that both mutations are completely penetrant and that children with early-onset CDI must be evaluated for AVP mutations even in the absence of this condition among relatives.…”

Section: Discussionmentioning

confidence: 99%

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Early-onset central diabetes insipidus is associated with de novo arginine vasopressin–neurophysin II or Wolfram syndrome 1 gene mutations

Perrotta

Iorgi

Ragione

et al. 2015

European Journal of Endocrinology

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Objective: Idiopathic early-onset central diabetes insipidus (CDI) might be due to mutations of arginine vasopressinneurophysin II (AVP-NPII (AVP)) or wolframin (WFS1) genes. Design and methods: Sequencing of AVP and WFS1 genes was performed in nine children with CDI, aged between 9 and 68 months, and negative family history for polyuria and polydipsia. Results: Two patients carried a mutation in the AVP gene: a heterozygous G-to-T transition at nucleotide position 322 of exon 2 (c.322GOT) resulting in a stop codon at position 108 (p.Glu108X), and a novel deletion from nucleotide 52 to 54 (c.52_54delTCC) producing a deletion of a serine at position 18 (p.Ser18del) of the AVP pre-prohormone signal peptide. A third patient carried two heterozygous mutations in the WFS1 gene localized on different alleles. The first change was A-to-G transition at nucleotide 997 in exon 8 (c.997AOG), resulting in a valine residue at position 333 in place of isoleucine (p.Ile333Val). The second novel mutation was a 3 bp insertion in exon 8, c.2392_2393insACG causing the addition of an aspartate residue at position 797 and the maintenance of the correct open reading frame (p. Asp797_Val798insAsp). While similar WFS1 protein levels were detected in fibroblasts from healthy subjects and from the patient and his parents, a major sensitivity to staurosporine-induced apoptosis was observed in the patient fibroblasts as well as in patients with Wolfram syndrome. Conclusions: Early-onset CDI is associated with de novo mutations of the AVP gene and with hereditary WFS1 gene changes. These findings have valuable implications for management and genetic counseling.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Early-onset central diabetes insipidus is associated with de novo arginine vasopressin–neurophysin II or Wolfram syndrome 1 gene mutations

Perrotta

Iorgi

Ragione

et al. 2015

European Journal of Endocrinology

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“…The protein toxicity and overload in the endoplasmic reticulum are molecular defects already known to be involved in congenital diabetes insipidus, where the disease begins after the neonatal period. Indeed, this delay represents the time to destroy vasopressin-secreting neurons (21). The INS mutations associated with permanent early-infancy diabetes extend this concept demonstrated in diabetes insipidus to diabetes.…”

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confidence: 80%

Heterozygous Missense Mutations in the Insulin Gene Are Linked to Permanent Diabetes Appearing in the Neonatal Period or in Early Infancy

et al. 2008

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OBJECTIVE—Permanent neonatal diabetes (PND) is defined by chronic hyperglycemia due to severe nonautoimmune insulin deficiency diagnosed in the first months of life. Several genes, including KCNJ11 and ABCC8, which encode the two subunits of the ATP-sensitive K+ channel (KATP channel) can cause PND. Mutations in the insulin (INS) gene have been recently described in families with neonatal diabetes. Our study aimed to investigate the genetic anomalies and clinical heterogeneity in PND patients who are negative for a KATP channel mutation. RESEARCH DESIGN AND METHODS—We screened the INS gene by direct sequencing in 38 PND patients and in one child with nonautoimmune early-infancy diabetes, where no mutation in GCK, KCNJ11, and ABCC8 was identified. A detailed clinical phenotyping of the patients was carried out to specify the diabetes features in those found with an INS mutation. RESULTS—We identified three missense mutations in the INS gene in four probands. Two of four mutations were inherited in a dominant manner, and the familial description evidenced a marked variability in age of diagnosis and disease progression. In our cohort, the INS mutations may represent ∼10% of all permanent neonatal diabetes cases, having a later presentation of diabetes and no associated symptoms compared with cases with KATP channel mutations. CONCLUSIONS—Heterozygous INS gene mutations can cause isolated permanent early-infancy diabetes and should be assessed in neonatal as well as in childhood diabetes appearing like type 1, when autoimmune markers are absent. New pharmacogenomic strategies may be applicable, since residual β-cell function is still present in some patients.

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“…Mutant AVP-C67X also binds to the wild-type AVP, and the heterodimers are retained in the endoplasmic reticulum (14)(15)(16)(17). It has been hypothesized that the accumulated mutant AVP heterodimers are cytotoxic, causing gradual but progressive loss of viable neurosecretory neurons, finally leading to AVP deficiency.…”

Section: Discussionmentioning

confidence: 99%

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

Fost¹,

Trotsenburg²,

Santen³

et al. 2011

European Journal of Endocrinology

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Background: 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. Case: 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.322GOT (p.?/p.Glu108X) in Exon 2 of the AVP-NPII gene in both mother and son. Discussion: 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.

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A murine model of autosomal dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-producing neurons

Cited by 45 publications

References 57 publications

Early-onset central diabetes insipidus is associated with de novo arginine vasopressin–neurophysin II or Wolfram syndrome 1 gene mutations

Early-onset central diabetes insipidus is associated with de novo arginine vasopressin–neurophysin II or Wolfram syndrome 1 gene mutations

Heterozygous Missense Mutations in the Insulin Gene Are Linked to Permanent Diabetes Appearing in the Neonatal Period or in Early Infancy

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

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