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)

Abstract

Objective: To study clinical, morphological and molecular characteristics in a Swiss family with autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI). Participants and methods: A 15-month-old girl presenting with symptoms of polydipsia and polyuria was investigated by water deprivation test. Evaluation of the family revealed three further family members with symptomatic vasopressin-de®cient diabetes insipidus. T1-weighted magnetic resonance images of the posterior pituitary were taken in two affected adult family members and molecular genetic analysis was performed in all affected individuals. Results: The water deprivation test in the 15-month-old child con®rmed the diagnosis of vasopressinde®cient diabetes insipidus and the pedigree was consistent with autosomal dominant inheritance. The characteristic bright spot of the normal vasopressin-containing neurophypophysis was absent in both adults with adFNDI. Direct sequence analysis revealed a new deletion (177±179DCGC) in exon 2 of the AVP-NP II gene in all affected individuals. At the amino acid level, this deletion eliminates cysteine 59 (C59D) and substitutes alanine 60 by tryptophan (A60W) in the AVP-NP II precursor; interestingly, the remainder of the reading frame remains unchanged. According to the threedimensional structure of neurophysin, C59 is involved in a disulphide bond with C65. Conclusions: Deletion of C59 and substitution of A60W in the AVP-NP II precursor is predicted to disrupt one of the seven disulphide bridges required for correct folding of the neurophysin moiety and thus disturb the function of neurophysin as the vasopressin transport protein. These data are in line with the clinical and morphological ®ndings in the reported family with adFNDI.

Autosomal Dominant Neurohypophyseal Diabetes Insipidus in Two Families

“…Consistent with the results of Rutishauser et al [8] and others [25,26,27], all 3 investigated patients of the two families did not show the ‘bright spot’ in T 1 -weighted pituitary images. Signal intensity is discussed to correlate closely with posterior lobe function as it is suspected to result from neurovesicles in axon endings of AVP-producing neurons [8, 28].…”

Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon 4, which encodes three EGF-like domains

“…Impaired disulphide binding is well known as a reason for other disorders, for example, diabetes insipidus centralis with a less stable vasopressin precursor, which accumulates in the endoplasmic reticulum [26]. The mutations we found are very likely to cause MCKD2 in these patients, even if none of them is a frameshift or a nonsense mutation.…”

Misfolding of Mutated Vasopressin Causes ER-Retention and Activation of ER-Stress Markers in Neuro-2a Cells

“…The result is the retention of both normal and mutated provasopressin in the ER that correlates with an increase in the ER chaperone BiP, a marker for the unfolded protein response [64, 65]. Markers for ER-stress associated apoptosis, i.e., caspase 12 and CHOP as induced by the expression of the two pro-vasopressin mutants suggest that apoptosis may play a role in the disappearance of vasopressinergic neurons observed in familial neurohypophyseal diabetes insipidus [1, 66, 67]. …”