Familial neurohypophyseal diabetes insipidus: clinical, genetic and functional studies of novel mutations in the arginine vasopressin gene.
Pituitary
; 24(3): 400-411, 2021 Jun.
Article
en En
| MEDLINE
| ID: mdl-33433888
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Diabetes Insípida Neurogénica
/
Diabetes Insípida
/
Diabetes Mellitus
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Pituitary
Asunto de la revista:
ENDOCRINOLOGIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Portugal