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

Abstract

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.

Growth retardation in untreated autosomal dominant familial neurohypophyseal diabetes insipidus caused by one recurring and two novel mutations in the vasopressin-neurophysin II gene

“…Maghnie et al (19) reported this finding in one of five children with adFNDI. We have reported on one case of partial empty sella among ten patients with adFNDI from three families (26). Melo et al described a child with adFNDI and a hypoplastic anterior pituitary with normal anterior pituitary function (27).…”

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

“…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. Although the most frequent form of familial CDI by far is the autosomal dominant condition (3), to our knowledge, de novo dominant mutations of the AVP gene have been reported as recurrent mutations in three families (17).…”

Diabetes Insipidus – Diagnosis and Management

“…It is worth pointing out that extrapituitary localizations of LCH including the chest or liver may become evident after the onset of CDI [32]. Rarely, de novo mutations of theAVP-NPII gene are responsible for some idiopathic forms of CDI associated with normal PS size [33,34]. …”

“…7, table 2) [1,13,27,40,41,42,56,57]. Dynamic MRI can help identify cases of CDI and normal PS size associated with abnormal blood supply to the posterior pituitary [33,58]. Diagnostic flowcharts for polyuria, polydipsia and CDI are reported in figures 8 and 9.…”