Familial neurohypophyseal diabetes insipidus: clinical, genetic and functional studies of novel mutations in the arginine vasopressin gene

• Published in: Pituitary 2021-06, Vol.24 (3), p.400-411
• Main Authors: Alvelos, Maria Inês, Francisco, Ângela, Gomes, Leonor, Paiva, Isabel, Melo, Miguel, Marques, Pedro, Gama-de-Sousa, Susana, Carreiro, Sofia, Quintela, Telma, Gonçalves, Isabel, Lemos, Manuel Carlos
• Format: Article
• Language: English
• Subjects: Argipressin; Children; Coding; Diabetes; Diabetes insipidus; Endocrinology; Etiology; Expression vectors; Genotypes; Human Physiology; Intracellular; Medicine; Medicine & Public Health; Missense mutation; Mutants; Mutation; Neural stem cells; Neurophysin; Nonsense mutation; Phenotypes; Pituitary (posterior); Polydipsia; Polyuria; Toxicity; Transfection; Vasopressin
• ISSN: 1386-341X; 1573-7403
• DOI: 10.1007/s11102-020-01119-y

Purpose Familial neurohypophyseal diabetes insipidus (FNDI) is a rare disorder characterized by childhood-onset progressive polyuria and polydipsia due to mutations in the arginine vasopressin ( AVP ) gene. The aim of the study was to describe the clinical and molecular characteristics of families with neurohypophyseal diabetes insipidus. Methods Five Portuguese families with autosomal dominant FNDI underwent sequencing of the AVP gene and the identified mutations were functionally characterized by in vitro studies. Results Three novel and two recurrent heterozygous mutations were identified in the AVP gene. These consisted of one initiation codon mutation in the signal peptide coding region (c.2T > C, p.Met1?), three missense mutations in the neurophysin II (NPII) coding region (c.154T > C, p.Cys52Arg; c.289C > G, p.Arg97Gly; and c.293G > C, p.Cys98Ser), and one nonsense mutation in the NPII coding region (c.343G > T, p.Glu115Ter). In vitro transfection of neuronal cells with expression vectors containing each mutation showed that the mutations resulted in intracellular retention of the vasopressin prohormone. Patients showed progressive symptoms of polyuria and polydipsia, but with wide variability in severity and age at onset. No clear genotype–phenotype correlation was observed. Conclusion The intracellular accumulation of mutant vasopressin precursors supports the role of cellular toxicity of the mutant proteins in the etiology of the disorder and explains the progressive onset of the disorder. These findings further expand the AVP mutational spectrum in FNDI and contribute to the understanding of the molecular pathogenic mechanisms involved in FNDI.