Familial neurohypophyseal diabetes insipidus in 13 kindreds and 2 novel mutations in the vasopressin gene

Abstract

Background Autosomal dominant neurohypophyseal diabetes insipidus (adNDI) is caused by arginine vasopressin (AVP) deficiency resulting from mutations in the AVP-NPII gene encoding the AVP preprohormone. Aim To describe the clinical and molecular features of Italian unrelated families with central diabetes insipidus. Patients and methods We analyzed AVP-NPII gene in 13 families in whom diabetes insipidus appeared to be segregating. Results Twenty-two patients were found to carry a pathogenic AVP-NPII gene mutation. Two novel c.173 G>C (p.Cys58Ser) and c.215 C>A (p.Ala72Glu) missense mutations and additional eight different mutations previously described were identified; nine were missense and one non-sense mutation. Most mutations (eight out of ten) occurred in the region encoding for the NPII moiety; two mutations were detected in exon 1. No mutations were found in exon 3. Median age of onset was 32.5 months with a variability within the same mutation (3 to 360 months). No clear genotype–phenotype correlation has been observed, except for the c.55 G>A (p.Ala19Thr) mutation, which led to a later onset of disease (median age 120 months). Brain magnetic resonance imaging (MRI) revealed the absence of posterior pituitary hyperintensity in 8 out of 15 subjects, hypointense signal in 4 and normal signal in 2. Follow-up MRI showed the disappearance of the posterior pituitary hyperintensity after 6 years in one case. Conclusion adNDI is a progressive disease with a variable age of onset. Molecular diagnosis and counseling should be provided to avoid unnecessary investigations and to ensure an early and adequate treatment.

Central Diabetes Insipidus Caused by Arginine Vasopressin Gene Mutation: Report of a Novel Mutation and Review of Literature

“…It is also suspected that the mutations interfere with the protein folding of the preprohormone, for example by impairing the binding between AVP and NPII. This might be the result of replacement or introduction of cysteine residues or, as already mentioned, the introduction of a stop codon [37,40]. Replacement of one of the 14 cysteine residues present in the NPII moiety has been found in a number of FNDI cases [8].…”

“…FNDI accounts for less than 10 % of diabetes insipidus cases seen in clinical practice [50], and is, with only a few exceptions, transmitted by autosomal dominant inheritance due to variants in one allele of the AVP gene [51]. The clinical occurrence of signs and symptoms is between the first and sixth year of life [40]. However, there are some cases where the age of onset is delayed [40].…”

“…The clinical occurrence of signs and symptoms is between the first and sixth year of life [40]. However, there are some cases where the age of onset is delayed [40].…”

A Partial Phenotype of adFNDI Related to the Signal Peptide c.55G>A Variant of the AVP Gene

“…The c.55G>A variant of the AVP gene is one of the most common disease-causing mutation described in adFNDI, as already described in many unrelated families in Denmark, the U.S., Asia, and elsewhere in Europe [18]. The p.Ala19Thr replacement is among neutral amino acids and may potentially cause only a mild effect on the biochemical features of the mature protein, thus inducing an exceptional delayed clinical onset of the inherited condition, which does not necessarily manifest at birth or in early infancy, as it could remain silent for up to 10 years after birth in several kindreds [19]. An older child's age at the time of clinical onset may also be due to underestimation of disease, especially in families with many affected members, where the production of large amounts of urine and persistent thirst are often regarded as "physiological" traits [19].…”

“…The p.Ala19Thr replacement is among neutral amino acids and may potentially cause only a mild effect on the biochemical features of the mature protein, thus inducing an exceptional delayed clinical onset of the inherited condition, which does not necessarily manifest at birth or in early infancy, as it could remain silent for up to 10 years after birth in several kindreds [19]. An older child's age at the time of clinical onset may also be due to underestimation of disease, especially in families with many affected members, where the production of large amounts of urine and persistent thirst are often regarded as "physiological" traits [19]. In rare cases, the documented adFNDI phenotype is partial, and the affected patients can concentrate their urine quite sufficiently during a standard fluid deprivation test, as occurred in our young adult index patient and two female adolescent Slovak twins of 17 years of age [17].…”