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Early-onset central diabetes insipidus is associated with de novo arginine vasopressin–neurophysin II or Wolfram syndrome 1 gene mutations

2015; Oxford University Press; Volume: 172; Issue: 4 Linguagem: Inglês

10.1530/eje-14-0942

1479-683X

Silverio Perrotta, Natascia Di Iorgi, Fulvio Della Ragione, Saverio Scianguetta, Adriana Borriello, Anna Elsa Maria Allegri, Marcella Ferraro, Claudia Santoro, Flavia Napoli, Annalisa Calcagno, Marta Giaccardi, Marco Cappa, Maria Carolina Salerno, Domenico Cozzolino, Mohamad Maghnie,

Neuroendocrine regulation and behavior

Objective Idiopathic early-onset central diabetes insipidus (CDI) might be due to mutations of arginine vasopressin–neurophysin II ( AVP–NPII ( AVP )) or wolframin ( WFS1 ) genes. Design and methods Sequencing of AVP and WFS1 genes was performed in nine children with CDI, aged between 9 and 68 months, and negative family history for polyuria and polydipsia. Results Two patients carried a mutation in the AVP gene: a heterozygous G-to-T transition at nucleotide position 322 of exon 2 (c.322G>T) resulting in a stop codon at position 108 (p.Glu108X), and a novel deletion from nucleotide 52 to 54 (c.52_54delTCC) producing a deletion of a serine at position 18 (p.Ser18del) of the AVP pre-prohormone signal peptide. A third patient carried two heterozygous mutations in the WFS1 gene localized on different alleles. The first change was A-to-G transition at nucleotide 997 in exon 8 (c.997A>G), resulting in a valine residue at position 333 in place of isoleucine (p.Ile333Val). The second novel mutation was a 3 bp insertion in exon 8, c.2392_2393insACG causing the addition of an aspartate residue at position 797 and the maintenance of the correct open reading frame (p. Asp797_Val798insAsp). While similar WFS1 protein levels were detected in fibroblasts from healthy subjects and from the patient and his parents, a major sensitivity to staurosporine-induced apoptosis was observed in the patient fibroblasts as well as in patients with Wolfram syndrome. Conclusions Early-onset CDI is associated with de novo mutations of the AVP gene and with hereditary WFS1 gene changes. These findings have valuable implications for management and genetic counseling.