Familial Neurohypophysial Diabetes Insipidus in a Large Dutch Kindred: Effect of the Onset of Diabetes on Growth in Children and Cell Biological Defects of the Mutant Vasopressin Prohormone1
Marga Nijenhuis2,
Erica L. T. van den Akker2,3,
Robbert Zalm,
Anton A. M. Franken,
Andre P. Abbes,
Henk Engel,
David de Wied and
J. Peter H. Burbach
Isala Klinieken Zwolle, Departments of Pediatrics (E.L.T.v.d.A.),
Internal Medicine (A.A.M.F.), Clinical Chemistry (A.P.A., H.E.), 8025
AB Zwolle, The Netherlands; and Rudolf Magnus Institute for
Neurosciences, Department of Medical Pharmacology, Utrecht University
(M.N., R.Z., D.d.W., J.P.H.B.), 3508 TA Utrecht, The Netherlands
Address all correspondence and requests for reprints to: Dr. J. Peter H. Burbach, Rudolf Magnus Institute for Neurosciences, Utrecht University, P.O. Box 80040, 3508 TA Utrecht, The Netherlands. E-mail:
j.p.h.burbach{at}med.uu.nl
Abstract
Familial neurohypophysial diabetes insipidus (FNDI) is an autosomal
dominanttrait in which expression of a mutant vasopressin prohormone
reducesvasopressin production. We investigated the NP85 CysGly
mutantvasopressin prohormone in a large kindred in The Netherlands.We
demonstrate that growth retardation is an important earlysign in two
children from this kindred, which recuperates bysubstitution therapy
with 1-desamino-8-D-arginine
vasopressin.To obtain clues about the basis for the
dominant inheritanceof FNDI, we analyzed the trafficking and
processing of the mutantvasopressin prohormone in cell lines by
metabolic labeling andimmunoprecipitation. The mutant vasopressin
prohormone was retainedin the endoplasmic reticulum and thus was not
processed to vasopressin.This defect was not caused by dimerization of
the vasopressinprohormone via its unpaired cysteine residue. High
level expressionof the mutant vasopressin prohormone in cell lines
resultedin strong accumulation in the endoplasmic reticulum and an
alteredmorphology of this organelle. We hypothesize that disturbance
ofthe endoplasmic reticulum results in dysfunction and ultimatelycell
death of the cells expressing the mutant prohormone. Ourdata support
the hypothesis that FNDI is a progressive neurodegenerativedisease
with delayed onset of symptoms. Its treatment requiresearly detection
of symptoms for which growth parameters areuseful.
This article has been cited by other articles:
A. Abu Libdeh, F. Levy-Khademi, M. Abdulhadi-Atwan, E. Bosin, M. Korner, P. C White, and D. H Zangen Autosomal recessive familial neurohypophyseal diabetes insipidus: onset in early infancy
Eur. J. Endocrinol.,
February 1, 2010;
162(2):
221 - 226.
[Abstract][Full Text][PDF]
M. Hayashi, H. Arima, N. Ozaki, Y. Morishita, M. Hiroi, N. Ozaki, H. Nagasaki, N. Kinoshita, M. Ueda, A. Shiota, et al. Progressive polyuria without vasopressin neuron loss in a mouse model for familial neurohypophysial diabetes insipidus
Am J Physiol Regulatory Integrative Comp Physiol,
May 1, 2009;
296(5):
R1641 - R1649.
[Abstract][Full Text][PDF]
J. H. Christensen, C. Siggaard, T. J. Corydon, G. L. Robertson, N. Gregersen, L. Bolund, and S. Rittig Differential Cellular Handling of Defective Arginine Vasopressin (AVP) Prohormones in Cells Expressing Mutations of the AVP Gene Associated with Autosomal Dominant and Recessive Familial Neurohypophyseal Diabetes Insipidus
J. Clin. Endocrinol. Metab.,
September 1, 2004;
89(9):
4521 - 4531.
[Abstract][Full Text][PDF]
J. T. Wahlstrom, M. J. Fowler, W. E. Nicholson, and W. J. Kovacs A Novel Mutation in the Preprovasopressin Gene Identified in a Kindred with Autosomal Dominant Neurohypophyseal Diabetes Insipidus
J. Clin. Endocrinol. Metab.,
April 1, 2004;
89(4):
1963 - 1968.
[Abstract][Full Text][PDF]
S. Rittig, C. Siggaard, M. Ozata, I. Yetkin, N. Gregersen, E. B. Pedersen, and G. L. Robertson Autosomal Dominant Neurohypophyseal Diabetes Insipidus due to Substitution of Histidine for Tyrosine2 in the Vasopressin Moiety of the Hormone Precursor
J. Clin. Endocrinol. Metab.,
July 1, 2002;
87(7):
3351 - 3355.
[Abstract][Full Text][PDF]
Gly
mutant vasopressin prohormone in a large kindred in The Netherlands. We
demonstrate that growth retardation is an important early sign in two
children from this kindred, which recuperates by substitution therapy
with 1-desamino-8-D-arginine
vasopressin. To obtain clues about the basis for the
dominant inheritance of FNDI, we analyzed the trafficking and
processing of the mutant vasopressin prohormone in cell lines by
metabolic labeling and immunoprecipitation. The mutant vasopressin
prohormone was retained in the endoplasmic reticulum and thus was not
processed to vasopressin. This defect was not caused by dimerization of
the vasopressin prohormone via its unpaired cysteine residue. High
level expression of the mutant vasopressin prohormone in cell lines
resulted in strong accumulation in the endoplasmic reticulum and an
altered morphology of this organelle. We hypothesize that disturbance
of the endoplasmic reticulum results in dysfunction and ultimately cell
death of the cells expressing the mutant prohormone. Our data support
the hypothesis that FNDI is a progressive neurodegenerative disease
with delayed onset of symptoms. Its treatment requires early detection
of symptoms for which growth parameters are useful. 
