La. Dimeglio et al., A missense mutation encoding Cys(67) -> Gly in neurophysin II is associated with early onset autosomal dominant neurohypophyseal diabetes insipidus, MOL GEN MET, 72(1), 2001, pp. 39-44
Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is an inheri
ted disorder in which progressive degeneration of magnocellular neurons of
the hypothalamus impairs production of arginine vasopressin (AVP). ADNDI is
caused by mutations in the arginine vasopressin-neurophysin II (AVP-NPII)
gene. These mutations are hypothesized to trigger neurodegeneration via dis
ruption of preproAVP-NPII processing. Affected individuals usually develop
diabetes insipidus between 1 and 6 years of age. Here we report a novel mut
ation of the AVP-NPII gene in a family with unusually early presentation of
ADNDI, The index case developed symptoms of diabetes insipidus at 1 month
of age, her mother at 9 months of age, and the maternal grandfather in earl
y childhood. Each was found to be heterozygous for the missense mutation 16
65T > G encoding the amino acid substitution C67G within NPII. This mutatio
n helps to define two homologous regions of the AVP-NPII precursor bounded
by disulfide bridges between C13 and C27 and between C61 and C73 that have
structural homology and contain the majority of amino acid substitutions as
sociated with ADNDI, The early onset of symptomatic diabetes insipidus in t
his family suggests that the C67G: substitution may be particularly deleter
ious to magnocellular neurons and may provide a valuable model for study of
dominantly inherited neurodegeneration. (C) 2001 Academic Press.