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.
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.
Rutishauser
Jonas
J
Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611, USA.
Kopp
Peter
P
Gaskill
Mary Beth
MB
Kotlar
Thomas J
TJ
Robertson
Gary L
GL
D000328:Adult; D019943:Amino Acid Substitution; D001483:Base Sequence / Q000235:genetics; D002648:Child; D003919:Diabetes Insipidus / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009481:Neurophysins / Q000235:genetics*; D010375:Pedigree; D010904:Pituitary Gland, Posterior / Q000473:pathology / Q000503:physiopathology*
D009481:Neurophysins