Silverio Perrotta1, Natascia Di Iorgi1, Fulvio Della Ragione1, Saverio Scianguetta1, Adriana Borriello1, Anna Elsa Maria Allegri1, Marcella Ferraro1, Claudia Santoro1, Flavia Napoli1, Annalisa Calcagno1, Marta Giaccardi1, Marco Cappa1, Maria Carolina Salerno1, Domenico Cozzolino1, Mohamad Maghnie2. 1. Dipartimento della Donnadel Bambino e di Chirurgia Generale e Specialistica, Second University of Naples, via De Crecchio 4, Naples, ItalyIstituto Giannina GasliniUniversity of Genova, 16147 Genova, ItalyDepartment of BiochemistryBiophysics, and General Pathology, Second University of Naples, via De Crecchio 7, Naples, ItalyIstituto Giannina GasliniLargo Gerolamo Gaslini 5, 16147 Genova, ItalyUnit of Endocrinology and DiabetologyBambino Gesù Children's Hospital, IRCCS, Rome, ItalyPediatric Endocrinology UnitDepartment of Translational Medical Sciences, University 'Federico II' of Naples, Naples, ItalyDivision of Internal MedicineSecond University of Naples, 80100 Naples, Italy. 2. Dipartimento della Donnadel Bambino e di Chirurgia Generale e Specialistica, Second University of Naples, via De Crecchio 4, Naples, ItalyIstituto Giannina GasliniUniversity of Genova, 16147 Genova, ItalyDepartment of BiochemistryBiophysics, and General Pathology, Second University of Naples, via De Crecchio 7, Naples, ItalyIstituto Giannina GasliniLargo Gerolamo Gaslini 5, 16147 Genova, ItalyUnit of Endocrinology and DiabetologyBambino Gesù Children's Hospital, IRCCS, Rome, ItalyPediatric Endocrinology UnitDepartment of Translational Medical Sciences, University 'Federico II' of Naples, Naples, ItalyDivision of Internal MedicineSecond University of Naples, 80100 Naples, Italy mohamadmaghnie@ospedale-gaslini.ge.it Mohamad.Maghnie@unige.it.
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 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.
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.
Authors: Gabriela Hrčková; Viktor Jankó; Jitka Kytnarová; Michaela Čižmárová; Markéta Tesařová; Ľudmila Košťálová; Daniela Virgová; Tomáš Dallos; Václav Hána; Jan Lebl; Jiří Zeman; László Kovács Journal: Eur J Pediatr Date: 2016-08-18 Impact factor: 3.183
Authors: Fabio Rotondo; Henriett Butz; Luis V Syro; George M Yousef; Antonio Di Ieva; Lina M Restrepo; Andres Quintanar-Stephano; Istvan Berczi; Kalman Kovacs Journal: Pituitary Date: 2016-08 Impact factor: 4.107