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


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.
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.
Silverio
S
Perrotta
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.
Natascia
N
Di Iorgi
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.
Fulvio Della
FD
Ragione
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.
Saverio
S
Scianguetta
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.
Adriana
A
Borriello
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.
Anna Elsa Maria
AE
Allegri
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.
Marcella
M
Ferraro
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.
Claudia
C
Santoro
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.
Flavia
F
Napoli
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.
Annalisa
A
Calcagno
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.
Marta
M
Giaccardi
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.
Marco
M
Cappa
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.
Maria Carolina
MC
Salerno
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.
Domenico
D
Cozzolino
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.
Mohamad
M
Maghnie
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002478:Cells, Cultured; D002648:Child; D015331:Cohort Studies; D020790:Diabetes Insipidus, Neurogenic / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D009481:Neurophysins / Q000235:genetics*; D011498:Protein Precursors / Q000235:genetics*; D014667:Vasopressins / Q000235:genetics*; D055815:Young Adult
C438657:AVP protein, human; D008565:Membrane Proteins; D009481:Neurophysins; D011498:Protein Precursors; C114987:wolframin protein; D014667:Vasopressins