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 amutation 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 fromnucleotide 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.

Early-onset central diabetes insipidus is associated with de novo arginine vasopressin-neurophysin II or Wolfram syndrome 1 gene mutations / Perrotta, Silverio; Di Iorgi, Natascia; Ragione, Fulvio Della; Scianguetta, Saverio; Borriello, Adriana; Allegri, Anna Elsa Maria; Ferraro, Marcella; Santoro, Claudia; Napoli, Flavia; Calcagno, Annalisa; Giaccardi, Marta; Cappa, Marco; Salerno, Mariacarolina; Cozzolino, Domenico; Maghnie, Mohamad. - In: EUROPEAN JOURNAL OF ENDOCRINOLOGY. - ISSN 0804-4643. - 172:4(2015), pp. 461-472. [10.1530/EJE-14-0942]

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

SANTORO, CLAUDIA;SALERNO, MARIACAROLINA;COZZOLINO, DOMENICO;
2015

Abstract

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 amutation 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 fromnucleotide 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.
2015
Early-onset central diabetes insipidus is associated with de novo arginine vasopressin-neurophysin II or Wolfram syndrome 1 gene mutations / Perrotta, Silverio; Di Iorgi, Natascia; Ragione, Fulvio Della; Scianguetta, Saverio; Borriello, Adriana; Allegri, Anna Elsa Maria; Ferraro, Marcella; Santoro, Claudia; Napoli, Flavia; Calcagno, Annalisa; Giaccardi, Marta; Cappa, Marco; Salerno, Mariacarolina; Cozzolino, Domenico; Maghnie, Mohamad. - In: EUROPEAN JOURNAL OF ENDOCRINOLOGY. - ISSN 0804-4643. - 172:4(2015), pp. 461-472. [10.1530/EJE-14-0942]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/614170
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