TY - JOUR
T1 - Early-onset central diabetes insipidus is associated with de novo arginine vasopressin-neurophysin II or Wolfram syndrome 1 gene mutations
AU - Perrotta, Silverio
AU - Di Iorgi, Natascia
AU - Della Ragione, Fulvio
AU - Scianguetta, Saverio
AU - Borriello, Adriana
AU - Allegri, Anna Elsa Maria
AU - Ferraro, Marcella
AU - Santoro, Claudia
AU - Napoli, Flavia
AU - Calcagno, Annalisa
AU - Giaccardi, Marta
AU - Cappa, Marco
AU - Salerno, Maria Carolina
AU - Cozzolino, Domenico
AU - Maghnie, Mohamad
PY - 2015/4/1
Y1 - 2015/4/1
N2 - 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.
AB - 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.
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U2 - 10.1530/EJE-14-0942
DO - 10.1530/EJE-14-0942
M3 - Article
C2 - 25740874
AN - SCOPUS:84927602507
VL - 172
SP - 461
EP - 472
JO - European Journal of Endocrinology
JF - European Journal of Endocrinology
SN - 0804-4643
IS - 4
ER -