CHARACTERIZATION OF THE MOLECULAR DEFECT IN THE VASOPRESSIN-NEUROPHYSIN II GENE IN A FAMILY WITH AUTOSOMAL DOMINANT NEUROHYPOPHYSEAL DIABETES INSIPIDUS

Abstract Context Familial neurohypophyseal diabetes insipidus is a rare disease produced by a deficiency in the secretion of antidiuretic hormone and is caused by mutations in the arginine vasopressin gene. Objective Clinical, biochemical, and genetic characterization of a group of patients clinically diagnosed with familial neurohypophyseal diabetes insipidus, 1 of the largest cohorts of patients with protein neurophysin II (AVP-NPII) gene alterations studied so far. Design The AVP-NPII gene was screened for mutations by PCR followed by direct Sanger sequencing in 15 different unrelated families from Spain. Results The 15 probands presented with polyuria and polydipsia as the most important symptoms at the time of diagnosis. In these patients, the disease was diagnosed at a median of 6 years of age. We observed 11 likely pathogenic variants. Importantly, 4 of the AVP-NPII variants were novel (p.(Tyr21Cys), p.(Gly45Ser), p.(Cys75Tyr), p.(Gly88Cys)). Conclusions Cytotoxicity seems to be due to consequences common to all the variants found in our cohort, which are not able to fold correctly and pass the quality control of the ER. In concordance, we found autosomal dominant familial neurohypophyseal diabetes insipidus in the 15 families studied.

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Clinical and molecular analysis of three families with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel and recurrent mutations in the vasopressin-neurophysin II gene

Acta Endocrinologica ◽

10.1530/eje.0.1460649 ◽

2002 ◽

pp. 649-656 ◽

Cited By ~ 26

Author(s):

J Rutishauser ◽

P Kopp ◽

MB Gaskill ◽

TJ Kotlar ◽

GL Robertson

Keyword(s):

Diabetes Insipidus ◽

Autosomal Dominant ◽

De Novo ◽

Index Patient ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Heterozygous Mutation ◽

Posterior Pituitary ◽

Recurrent Mutations ◽

Neurophysin Ii

OBJECTIVE: To test further the hypothesis that autosomal dominant neurohypophyseal diabetes insipidus (adFNDI) is caused by heterozygous mutations in the vasopressin-neurophysin II (AVP-NPII) gene that exert a dominant negative effect by producing a precursor that misfolds, accumulates and eventually destroys the neurosecretory neurons. METHODS: Antidiuretic function, magnetic resonance imaging (MRI) of the posterior pituitary and AVP-NPII gene analysis were performed in 10 affected members of three unreported families with adFNDI. RESULTS: As in previously studied patients, adFNDI apparently manifested after birth, was due to a partial or severe deficiency of AVP, and was associated with absence or diminution of the hyperintense MRI signal normally emitted by the posterior pituitary, and with a heterozygous mutation in the AVP-NPII gene. In family A, a transition 275G-->A, which predicts replacement of cysteine 92 by tyrosine (C92Y), was found in the index patient, but not in either parent, indicating that it arose de novo. The six affected members of family B had a transversion 160G-->C, which predicts replacement of glycine 54 by arginine (G54R). It appeared de novo in the oldest affected member, and was transmitted in a dominant manner. In family C, six of 15 living affected members were tested and all had a novel transition, 313T-->C, which predicts replacement of cysteine 105 by arginine (C105R). It, too, was transmitted in a dominant manner. As in other patients with adFNDI, the amino acids replaced by the mutations in these three families are known to be particularly important for correct and efficient folding of the precursor. CONCLUSIONS: These findings are consistent with the malfolding/toxicity hypothesis underlying the pathogenesis of adFNDI. Moreover, they illustrate the value of genetic analysis in all patients who develop idiopathic diabetes insipidus in childhood, even if no other family members are affected.

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A novel point mutation in the translation initiation codon of the pre- pro-vasopressin-neurophysin II gene: cosegregation with morphological abnormalities and clinical symptoms in autosomal dominant neurohypophyseal diabetes insipidus

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.81.1.192 ◽

1996 ◽

Vol 81 (1) ◽

pp. 192-198 ◽

Cited By ~ 15

Author(s):

J. Rutishauser

Keyword(s):

Diabetes Insipidus ◽

Point Mutation ◽

Translation Initiation ◽

Autosomal Dominant ◽

Clinical Symptoms ◽

Initiation Codon ◽

Morphological Abnormalities ◽

Translation Initiation Codon ◽

Neurophysin Ii

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

Clinical Endocrinology ◽

10.1111/cen.12129 ◽

2013 ◽

Vol 78 (6) ◽

pp. 920-925 ◽

Cited By ~ 3

Author(s):

Dan Ye ◽

FengQin Dong ◽

WeiQin Lu ◽

Zhe Zhang ◽

XunLiang Lu ◽

...

Keyword(s):

Diabetes Insipidus ◽

Missense Mutation ◽

Arginine Vasopressin ◽

Autosomal Dominant ◽

Chinese Family ◽

Neurophysin Ii

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

Acta Endocrinologica ◽

10.1530/eje-11-0048 ◽

2011 ◽

Vol 165 (1) ◽

pp. 161-165 ◽

Cited By ~ 9

Author(s):

M de Fost ◽

A S P van Trotsenburg ◽

H M van Santen ◽

E Endert ◽

C van den Elzen ◽

...

Keyword(s):

Diabetes Insipidus ◽

Arginine Vasopressin ◽

Water Deprivation ◽

Autosomal Dominant ◽

Novel Mutation ◽

Resonance Imaging ◽

Exon 2 ◽

Hyperintense Signal ◽

The Brain ◽

Neurophysin Ii

BackgroundFamilial 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.CaseA 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.DiscussionThis 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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