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

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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.

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Funding

This work was supported by the Portuguese Foundation for Science and Technology (PTDC/SAU-GMG/098419/2008).

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Author notes

  1. Maria Inês Alvelos

    Present address: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium

  2. Maria Inês Alvelos and Ângela Francisco should be regarded as joint first authors.

Authors and Affiliations

  1. CICS-UBI, Health Sciences Research Centre, University of Beira Interior, 6200-506, Covilha, Portugal

    Maria Inês Alvelos, Ângela Francisco, Telma Quintela, Isabel Gonçalves & Manuel Carlos Lemos

  2. Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de Coimbra, 3000-075, Coimbra, Portugal

    Leonor Gomes, Isabel Paiva & Miguel Melo

  3. Serviço de Endocrinologia, Instituto Português de Oncologia de Lisboa, 1099-023, Lisboa, Portugal

    Pedro Marques

  4. Serviço de Pediatria, Centro Hospitalar do Médio Ave, Unidade de V. N. Famalicão, 4761-917, Vila Nova de Famalicão, Portugal

    Susana Gama-de-Sousa

  5. Serviço de Patologia Clínica, Instituto Português de Oncologia de Coimbra, 3000-075, Coimbra, Portugal

    Sofia Carreiro

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Contributions

MIA: Methodology, Investigation, Writing—original draft. ÂF: Methodology, Investigation. LG: Resources. IP: Resources. MM: Resources. PM: Resources. SGS: Resources. SC: Investigation. TQ: Investigation. IG: Investigation. MCL: Conceptualization, Funding acquisition, Project administration, Supervision; Writing—review & editing.

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Correspondence to Manuel Carlos Lemos.

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The study was approved by the Ethics Committee of the Faculty of Health Sciences, University of Beira Interior (Ref: CE-FCS-2012-012).

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Alvelos, M.I., Francisco, Â., Gomes, L. et al. Familial neurohypophyseal diabetes insipidus: clinical, genetic and functional studies of novel mutations in the arginine vasopressin gene. Pituitary 24, 400–411 (2021). https://doi.org/10.1007/s11102-020-01119-y

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