Identification of a novel mutation in the arginine vasopressin-neurophysin II gene in familial central diabetes insipidus

Abstract

Familial central diabetes insipidus is an inherited disease of predominant autosomal dominant trait characterized by a deficiency of arginine vasopressin. The arginine vasopressin-neurophysin II ( AVP-NPII) gene consists of three exons and is located on chromosome 20p13 encoding for the precursor protein of AVP. We investigated two Caucasian families with a typical autosomal dominant trait of familial central diabetes insipidus, defined by deficiency of arginine vasopressin. After PCR amplification of exon 1 and exon 2/3, fragments were pooled and purified. Nucleotide sequencing was performed with the Taq DyeDeoxy-terminator cycle sequencing method using nested primers. Two mutations in the coding region of NPII were identified. In family C we found a heterozygous G ==> C missense mutation (AA61) in exon 2 leading to the substitution of cystein with serine. In family D a novel heterozygous nonsense mutation in exon 3 (AA 83, GAG ==> TAG) was indentified, leading to a stop codon instead of glutamine. Both mutations were confirmed by restriction analysis and were found in all affected but not in healthy family members or control subjects. We therefore have identified a missense mutation of the AVP-NPII gene and a novel mutation predicting a truncated protein.

Six novel mutations in the arginine vasopressin gene in 15 kindreds with autosomal dominant familial neurohypophyseal diabetes insipidus give further insight into the pathogenesis

“…17,32 The other six recurrent mutations were identified in only one kindred each ( Table 2, kindreds 7 -9 and 13 -15). None of these kindreds had any known relationship to the kindreds in which the same mutations have been described previously, namely the 279G4A (A19T) mutation identified in four American, a Japanese, a Danish, a Spanish, and a Brazilian kindred, 3,15,17,33 -36 the 280C4T (A19 V) mutation identified in two American, a Lebanese, a German, and a Japanese kindred, 10,11,17,37 the 1757G4C (G54R) mutation identified in a German and an American kindred, 13,38 the 1830A4G (E78G) mutation identified in an English kindred, 17 the 1873C4A (C92X) mutation identified in a Norwegian kindred, 17 and finally, the 1883G4T (G96C) mutation identified in an American kindred. 17 In one kindred ( Table 1, kindred 5), a mutation was identified in an unaffected 1-year-old child at risk for inheriting adFNDI (Figures 1 and 2).…”

“…The NP74 and NP84 mutations were originally published as NP73 13 and NP83, respectively. 10 proband inherited the mutation through his mother and maternal grandmother in whom it thus appeared to have been nonpenetrant or that his mother inherited the mutation from another male relative who was not the father of record. Since only two subjects, one affected and a newborn without clinical assessment, were studied, it is difficult to correlate the genotype and phenotype in the kindred.…”

The Novel Ser18del AVP Variant Causes Inherited Neurohypophyseal Diabetes Insipidus by Mechanisms Shared with Other Signal Peptide Variants

“…This variant has not been found in healthy subjects [10,[34][35][36][37][38][39][40][41][42], but it has recently been found as a de novo disease-associated variant in a single case with neurohypophyseal DI [20]. Not only did we demonstrate a clear molecular pathogenic effect of this variant in in vitro experiments, but we also found that the variant co-segregated with disease in 7 cases in 3 generations, thereby adding solid evidence that the Ser18del variant is indeed causing inherited FNDI.…”

Preventing and Correcting Communicable and Non-Communicable Chronic Disease via Amlexanox – Dual ‘No-Nonsense’ and Inflammatory Axis Targeting

“…A novel nonsense mutation, p.W296x of A VPR2, eliminated measurable excretion of AQP2 yet a missense mutation, p.V88M in other family members still allowed for AQP2 detection in the excretion. Nonsense mutation produced a more severe phenotype [173].…”