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Heterogeneity in Clinical Manifestation of Autosomal Dominant Neurohypophyseal Diabetes Insipidus Caused by a Mutation Encoding Ala^-1Val in the Signal Peptide of the Arginine Vasopressin/Neurophysin II/Copeptin Precursor¹

Division of Endocrinology, Children’s Hospital Medical Center (D.R.R., E.K.G), Cincinnati, Ohio 45229-3039; the Department of Endocrinology, Hotel-Dieu de France (R.M., G.H.), Beirut, Lebanon; Department of Pediatrics, Vanderbilt University School of Medicine (M.R.S.K., J.A.P), Nashville, Tennessee 37232-2578; and the Division of Endocrinology, St. Luke’s Medical Center (J.W.F.), Milwaukee, Wisconsin 53215

Address all correspondence and requests for reprints to: David Repaske, Ph.D., M.D., NWM-1 TCHRF, Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039. E-mail: repaskdr{at}ucunix.san.uc.edu

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a familial form of diabetes insipidus due to progressive vasopressin deficiency with onset typically at 1–6 yr of age. Affected individuals demonstrate specific degeneration of the vasopressinergic magnocellular neurons in the hypothalamic supraoptic and paraventricular nuclei and loss of the posterior pituitary bright spot on magnetic resonance imaging. The genetic locus of ADNDI is the arginine vasopressin-neurophysin II (AVP-NPII) gene. Mutations that cause ADNDI have been found to occur both within the signal peptide of the prepro-AVP-NPII precursor and within the coding sequence for neurophysin II, but not within the coding sequence for AVP itself. We evaluated the AVP-NPII genes in two independent families with ADNDI and identified a mutation (C²⁸⁰T) in the coding sequence for the signal peptide of the prepro-AVP-NPII precursor in both families. This mutation encodes an AlaVal substitution at the C-terminus of the signal peptide (-1 amino acid). This mutation predicts the complete inability of signal peptidase to cleave the signal peptide from the preproprecursor and supports the hypothesis that the progressive neural degeneration that underlies ADNDI is caused by accumulation of malprocessed precursor. However, considerable heterogeneity in the age of onset (1–28 yr of age) and the severity of diabetes insipidus among affected members of these two families suggests that additional factors modulate the rate and extent of progression of the neurodegeneration that results from this one specific ADNDI mutation.

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