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A Novel Mutation in the Preprovasopressin Gene Identified in a Kindred with Autosomal Dominant Neurohypophyseal Diabetes Insipidus

Division of Diabetes, Endocrinology, and Metabolism (J.T.W., M.J.F., W.E.N., W.J.K.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and United States Department of Veterans Affairs (W.J.K.), Tennessee Valley Healthcare System, Nashville, Tennessee 37212

Address all correspondence and requests for reprints to: William J. Kovacs, M.D., Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University School of Medicine, Room 715 Preston Research Building, Nashville, Tennessee 37232. E-mail: william.kovacs{at}vanderbilt.edu.

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a defect in free water conservation caused by mutations in the single gene that encodes both vasopressin (VP) and its binding protein, neurophysin II (NP II). Most of the human mutations in this gene have been in the portion encoding the NP molecule; the resultant abnormal gene products are believed to cause cellular toxicity as improperly folded precursor molecules accumulate in the endoplasmic reticulum. We identified a new American kindred with ADNDI and found a novel mutation in the VP molecule. A 78-yr-old man was noted to have hypotonic polyuria and plasma hyperosmolarity; the urinary concentration defect was reversed by administration of VP. His symptomatology dated to childhood, and his family history was consistent with autosomal transmission of the polyuric syndrome, with affected members in three generations, including several females. Affected individuals were found to be heterozygous for a 3-bp deletion in exon 1 of arginine VP (AVP)-NP II, predicting a deletion of phenylalanine 3 (known to be critical for receptor binding) in the VP nonapeptide. Neuro 2A cells stably transfected with the mutant AVP-NP construct showed increased rates of apoptosis as assessed by flow cytometric methods. These observations support the concept that cellular toxicity of abnormal AVP-NP gene products underlies the development of ADNDI, and the data further demonstrate that mutations affecting the AVP moiety can result in initiation of these pathological processes.

This work was supported by a Merit Review Grant (to W.J.K.) from the United States Department of Veterans Affairs. Our studies used the resources of core laboratories of the Vanderbilt University Diabetes Research and Training Center (NIH Grant P60 DK020593). J.T.W. received support from the Vanderbilt University School of Medicine’s Medical Scholars Program.

Abbreviations: ADNDI, Autosomal dominant neurohypophyseal diabetes insipidus; AVP, arginine VP; ER, endoplasmic reticulum; NP II, neurophysin II; VP, vasopressin.

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