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

• Published in: The journal of clinical endocrinology and metabolism 2004-09, Vol.89 (9), p.4521-4531
• Main Authors: Christensen, Jane H., Siggaard, Charlotte, Corydon, Thomas J., Robertson, Gary L., Gregersen, Niels, Bolund, Lars, Rittig, Søren
• Format: Article
• Language: English
• Subjects: Arginine Vasopressin - biosynthesis; Arginine Vasopressin - genetics; Biological and medical sciences; Cells, Cultured; Diabetes Insipidus, Neurogenic - genetics; Endocrinopathies; Fundamental and applied biological sciences. Psychology; Humans; Hypothalamus. Hypophysis. Epiphysis (diseases); Medical sciences; Microscopy, Confocal; Mutation; Neurophysins - immunology; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Precipitin Tests; Vasopressins - metabolism; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2003-031813

An unusual mutation in the arginine vasopressin (AVP) gene, predicting a P26L amino acid substitution of the AVP prohormone, is associated with autosomal recessive familial neurohypophyseal diabetes insipidus (FNDI). To investigate whether the cellular handling of the P26L prohormone differed from that of the Y21H prohormone associated with autosomal dominant inheritance of FNDI, the mutations were examined by heterologous expression in cell lines. Immunoprecipitation demonstrated retarded processing and secretion of the Y21H prohormone, whereas the secretion of the P26L prohormone seemed to be unaffected. Confocal laser scanning microscopy showed accumulation of the Y21H prohormone in the endoplasmic reticulum, whereas the P26L prohormone and/or processed products were localized in secretory granules in the cellular processes. RIA analysis showed reduced amounts of immunoreactive Y21H-AVP and P26L-AVP in the cell culture medium. Thus, the recessive mutation does not seem to affect the intracellular trafficking but rather the final processing of the prohormone. Our results provide an important negative control in support of the hypothesis that autosomal dominant inheritance of FNDI is caused by mutations in the AVP gene that alter amino acid residues important for folding and/or dimerization of the neurophysin II moiety of the AVP prohormone and subsequent transport from the endoplasmic reticulum.