A Partial Phenotype of adFNDI Related to the Signal Peptide c.55G>A Variant of the <i>AVP</i> Gene
The autosomal dominant familial form of neurohypophyseal diabetes insipidus (adFNDI) is a rare inherited endocrine disorder characterized by hypotonic polyuria, severe thirst and polydipsia, which results from a deficient neurosecretion of the antidiuretic hormone, also known as arginine vasopressin...
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| Format: | Article |
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MDPI AG
2021-02-01
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| Series: | Endocrines |
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| Online Access: | https://www.mdpi.com/2673-396X/2/1/4 |
| _version_ | 1797396546671607808 |
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| author | Vera Tocci Maria Mirabelli Stefania Giuliano Eusebio Chiefari Jane Hagelskjær Knudsen Helene Kvistgaard Domenico La Torre Antonio Aversa Daniela Patrizia Foti Jane Hvarregaard Christensen Antonio Brunetti |
| author_facet | Vera Tocci Maria Mirabelli Stefania Giuliano Eusebio Chiefari Jane Hagelskjær Knudsen Helene Kvistgaard Domenico La Torre Antonio Aversa Daniela Patrizia Foti Jane Hvarregaard Christensen Antonio Brunetti |
| author_sort | Vera Tocci |
| collection | DOAJ |
| description | The autosomal dominant familial form of neurohypophyseal diabetes insipidus (adFNDI) is a rare inherited endocrine disorder characterized by hypotonic polyuria, severe thirst and polydipsia, which results from a deficient neurosecretion of the antidiuretic hormone, also known as arginine vasopressin (AVP). To date, adFNDI has been linked to more than 70 different heterozygous point mutations of the 2.5 kb <i>AVP</i> gene, encoding the composite precursor protein of AVP. A minority of disease-causing mutations, such as the common c.55G>A variant, are predicted to affect amino acid residues close to the signal peptide (SP) cleavage site, and result in abnormal post-translational processing and intracellular trafficking of AVP precursors exerting neurotoxic activity on vasopressinergic magnocellular neurons. Generally, SP variants cause a gradual decline in the neurohypophyseal secretion of AVP in small children, although a wide variability in clinical onset and severity of manifestations has been reported. For the first time, we describe a kindred from Calabria (Southern Italy) with adFNDI and document a partial clinical phenotype in one female young adult member of the family. Methods: A young adult woman was subjected to clinical, neuroradiological and genetic assessments for a mild, adolescent-onset, polyuric state at our Endocrinology Unit. Her family medical history revealed an early-onset (<12 years of age) occurrence of polyuria and polydipsia, which was successfully managed with high doses of oral desmopressin, and a typical adFNDI inheritance pattern that was seen over three generations. Results: In the index patient, the extensive hypertonic dehydration during fluid deprivation test elicited a prompt elevation of urine osmolality and diuresis contraction, indicative of a partial adFNDI phenotype. Diagnosis was confirmed by concordant hormonal tests and magnetic resonance imaging (MRI) evidence of a reduced hyperintense signal of the neurohypophysis, which was regarded as compatible with the depletion of the vasopressinergic magnocellular neurons. Direct DNA sequencing and restriction enzyme cleavage analysis revealed that a heterozygous c.55G>A transition, predicting a p.Ala19Thr replacement in the C-terminal region of SP, was the cause of adFNDI in the investigated kindred. Conclusions: The identification of the genetic cause of aFNDI in this Calabrian kindred provides further information and confirms the wide variability of disease onset and severity of manifestations related to SP variants of the <i>AVP</i> gene, supporting the need for genetic testing in all patients with familial occurrence of polyuria, regardless of their clinical and radiological phenotype. Even though sexual differences in the antidiuretic responses are documented, it is unclear whether female gender would attenuate clinical disease progression in the presence of a pathogenic c.55G>A mutation. |
| first_indexed | 2024-03-09T00:52:57Z |
| format | Article |
| id | doaj.art-cab26bb76f304a06bb2dc0b5ff022b75 |
| institution | Directory Open Access Journal |
| issn | 2673-396X |
| language | English |
| last_indexed | 2024-03-09T00:52:57Z |
| publishDate | 2021-02-01 |
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| record_format | Article |
| series | Endocrines |
| spelling | doaj.art-cab26bb76f304a06bb2dc0b5ff022b752023-12-11T17:07:35ZengMDPI AGEndocrines2673-396X2021-02-0121374310.3390/endocrines2010004A Partial Phenotype of adFNDI Related to the Signal Peptide c.55G>A Variant of the <i>AVP</i> GeneVera Tocci0Maria Mirabelli1Stefania Giuliano2Eusebio Chiefari3Jane Hagelskjær Knudsen4Helene Kvistgaard5Domenico La Torre6Antonio Aversa7Daniela Patrizia Foti8Jane Hvarregaard Christensen9Antonio Brunetti10Unit of Endocrinology, Azienda Ospedaliera Mater-Domini, 88100 Catanzaro, ItalyDepartment of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, ItalyUnit of Endocrinology, Azienda Ospedaliera Mater-Domini, 88100 Catanzaro, ItalyDepartment of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, ItalyDepartment of Pediatrics and Adolescent Medicine, Aarhus University Hospital, 8000 Aarhus, DenmarkDepartment of Pediatrics and Adolescent Medicine, Aarhus University Hospital, 8000 Aarhus, DenmarkUnit of Neurosurgery, Azienda Ospedaliera Mater-Domini, 88100 Catanzaro, ItalyUnit of Endocrinology, Azienda Ospedaliera Mater-Domini, 88100 Catanzaro, ItalyDepartment of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, ItalyDepartment of Biomedicine, Aarhus University, 8000 Aarhus, DenmarkUnit of Endocrinology, Azienda Ospedaliera Mater-Domini, 88100 Catanzaro, ItalyThe autosomal dominant familial form of neurohypophyseal diabetes insipidus (adFNDI) is a rare inherited endocrine disorder characterized by hypotonic polyuria, severe thirst and polydipsia, which results from a deficient neurosecretion of the antidiuretic hormone, also known as arginine vasopressin (AVP). To date, adFNDI has been linked to more than 70 different heterozygous point mutations of the 2.5 kb <i>AVP</i> gene, encoding the composite precursor protein of AVP. A minority of disease-causing mutations, such as the common c.55G>A variant, are predicted to affect amino acid residues close to the signal peptide (SP) cleavage site, and result in abnormal post-translational processing and intracellular trafficking of AVP precursors exerting neurotoxic activity on vasopressinergic magnocellular neurons. Generally, SP variants cause a gradual decline in the neurohypophyseal secretion of AVP in small children, although a wide variability in clinical onset and severity of manifestations has been reported. For the first time, we describe a kindred from Calabria (Southern Italy) with adFNDI and document a partial clinical phenotype in one female young adult member of the family. Methods: A young adult woman was subjected to clinical, neuroradiological and genetic assessments for a mild, adolescent-onset, polyuric state at our Endocrinology Unit. Her family medical history revealed an early-onset (<12 years of age) occurrence of polyuria and polydipsia, which was successfully managed with high doses of oral desmopressin, and a typical adFNDI inheritance pattern that was seen over three generations. Results: In the index patient, the extensive hypertonic dehydration during fluid deprivation test elicited a prompt elevation of urine osmolality and diuresis contraction, indicative of a partial adFNDI phenotype. Diagnosis was confirmed by concordant hormonal tests and magnetic resonance imaging (MRI) evidence of a reduced hyperintense signal of the neurohypophysis, which was regarded as compatible with the depletion of the vasopressinergic magnocellular neurons. Direct DNA sequencing and restriction enzyme cleavage analysis revealed that a heterozygous c.55G>A transition, predicting a p.Ala19Thr replacement in the C-terminal region of SP, was the cause of adFNDI in the investigated kindred. Conclusions: The identification of the genetic cause of aFNDI in this Calabrian kindred provides further information and confirms the wide variability of disease onset and severity of manifestations related to SP variants of the <i>AVP</i> gene, supporting the need for genetic testing in all patients with familial occurrence of polyuria, regardless of their clinical and radiological phenotype. Even though sexual differences in the antidiuretic responses are documented, it is unclear whether female gender would attenuate clinical disease progression in the presence of a pathogenic c.55G>A mutation.https://www.mdpi.com/2673-396X/2/1/4AVPsignal peptideadFNDIrare endocrine diseasesgender medicine |
| spellingShingle | Vera Tocci Maria Mirabelli Stefania Giuliano Eusebio Chiefari Jane Hagelskjær Knudsen Helene Kvistgaard Domenico La Torre Antonio Aversa Daniela Patrizia Foti Jane Hvarregaard Christensen Antonio Brunetti A Partial Phenotype of adFNDI Related to the Signal Peptide c.55G>A Variant of the <i>AVP</i> Gene Endocrines AVP signal peptide adFNDI rare endocrine diseases gender medicine |
| title | A Partial Phenotype of adFNDI Related to the Signal Peptide c.55G>A Variant of the <i>AVP</i> Gene |
| title_full | A Partial Phenotype of adFNDI Related to the Signal Peptide c.55G>A Variant of the <i>AVP</i> Gene |
| title_fullStr | A Partial Phenotype of adFNDI Related to the Signal Peptide c.55G>A Variant of the <i>AVP</i> Gene |
| title_full_unstemmed | A Partial Phenotype of adFNDI Related to the Signal Peptide c.55G>A Variant of the <i>AVP</i> Gene |
| title_short | A Partial Phenotype of adFNDI Related to the Signal Peptide c.55G>A Variant of the <i>AVP</i> Gene |
| title_sort | partial phenotype of adfndi related to the signal peptide c 55g a variant of the i avp i gene |
| topic | AVP signal peptide adFNDI rare endocrine diseases gender medicine |
| url | https://www.mdpi.com/2673-396X/2/1/4 |
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