Maria Inês Alvelos1,2, Ângela Francisco1, Leonor Gomes3, Isabel Paiva3, Miguel Melo3, Pedro Marques4, Susana Gama-de-Sousa5, Sofia Carreiro6, Telma Quintela1, Isabel Gonçalves1, Manuel Carlos Lemos7. 1. CICS-UBI, Health Sciences Research Centre, University of Beira Interior, 6200-506, Covilha, Portugal. 2. ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium. 3. Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de Coimbra, 3000-075, Coimbra, Portugal. 4. Serviço de Endocrinologia, Instituto Português de Oncologia de Lisboa, 1099-023, Lisboa, Portugal. 5. Serviço de Pediatria, Centro Hospitalar do Médio Ave, Unidade de V. N. Famalicão, 4761-917, Vila Nova de Famalicão, Portugal. 6. Serviço de Patologia Clínica, Instituto Português de Oncologia de Coimbra, 3000-075, Coimbra, Portugal. 7. CICS-UBI, Health Sciences Research Centre, University of Beira Interior, 6200-506, Covilha, Portugal. mclemos@fcsaude.ubi.pt.
Abstract
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.
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.
Authors: M Ozata; C Tayfun; K Kurtaran; I Yetkin; Z Beyhan; A Corakci; S Cağlayan; A Alemdaroglu; M A Gündogan Journal: Eur Radiol Date: 1997 Impact factor: 5.315
Authors: Mirjam Christ-Crain; Daniel G Bichet; Wiebke K Fenske; Morris B Goldman; Soren Rittig; Joseph G Verbalis; Alan S Verkman Journal: Nat Rev Dis Primers Date: 2019-08-08 Impact factor: 52.329
Authors: Peter D Stenson; Matthew Mort; Edward V Ball; Katy Evans; Matthew Hayden; Sally Heywood; Michelle Hussain; Andrew D Phillips; David N Cooper Journal: Hum Genet Date: 2017-03-27 Impact factor: 4.132