A novel mutation in the preprovasopressin gene identified in a kindred with autosomal dominant neurohypophyseal diabetes insipidus.

Abstract

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.

• Authors: Justin T Wahlstrom, Michael J Fowler, Wendell E Nicholson, William J Kovacs
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 89 Issue 4 Pg. 1963-8 (Apr 2004) ISSN: 0021-972X [Print] United States
• PMID: 15070970 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• AVP protein, human
• Neurophysins
• Protein Precursors
• preprovasopressin
• Vasopressins

Topics

• Aged
• Apoptosis
• Base Sequence
• Diabetes Insipidus, Neurogenic (genetics, physiopathology)
• Flow Cytometry
• Gene Deletion
• Genes, Dominant
• Heterozygote
• Humans
• Male
• Molecular Sequence Data
• Mutation
• Neurophysins (genetics)
• Pedigree
• Polyuria (genetics)
• Protein Precursors (genetics)
• Vasopressins (genetics)