Genetic Basis of Familial Neurohypophyseal Diabetes Insipidus

Autosomal dominant neurohypophyseal diabetes insipidus in a Swiss family, caused by a novel mutation (C59Delta/A60W) in the neurophysin moiety of prepro-vasopressin-neurophysin II (AVP-NP II)

“…3). The structural consequence of this mutation (C59D, A60W) in the neurophysin moiety is expected to alter correct folding of the AVP-NP II precursor by eliminating a disulphide bridge (C59±C65) (1,18,36,37). It is noteworthy that the only known frameshift mutation in the AVP-NP II gene identi®ed to date occurred in the Brattleboro rat and is associated with a recessive mechanism of disease (38).…”

“…Incorrect folding by elimination or introduction of cysteine residues is a commonly observed mechanism underlying abnormal folding of AVP-NP II in adFNDI (1,15). Recently, a report of the expression of mutated AVP-NP II in different transfected cells documented retention of the mutated precursor molecule in the endoplasmic reticulum (17, 39±41).…”

“…Furthermore, there is evidence for the toxicity of mutant precursors or their degradation products in cultured neuro2A neuroblastoma cells (40). Other mutations in the NP II moiety are believed to affect¯exibility or rigidity of the molecule, or they may alter the structure of the binding pocket and thus impair binding of AVP to its carrier protein (1). Mutations in the signal peptide impair or misdirect cleavage of the signal peptide from the N-terminus of AVP (1, 41, 42).…”

“…Overall, the fact that all the mutations affecting the signal peptide or the neurophysin moiety result in amino acid substitutions or deletions of residues that are important for processing, folding or oligomerization of the precursor suggests a possible unifying molecular mechanism for the development of the disease (1,18).…”

“…Various heterozygous mutations in the coding sequence of the AVP-NP II gene have been identi®ed in patients with adFNDI (1). The AVP-NP II gene is located on chromosome 20p13 and consists of three exons.…”