ESPE Abstracts (2014) 82 FC11.3

Early-Onset Central Diabetes Insipidus is Associated with De Novo Arginine Vasopressin-Neurophysin II or Wolfram Syndrome 1 Gene Mutations

Anna Elsa Maria Allegria, Natascia Di Iorgia,b, Silverio Perrottac, Fulvio Della Ragioned, Saverio Scianguettac, Adriana Borriellod, Marcella Ferraroc, Claudia Santoroc, Annalisa Calcagnoa, Flavia Napolia, Marta Giaccardia,b, Marco Cappae, Maria Carolina Salernof & Mohamad Maghniea,b

aDepartment of Pediatrics, Istituto Giannina Gaslini, Genoa, Italy; bUniversity of Genoa, Genoa, Italy; cDipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Second University of Naples, Naples, Italy; dDepartment of Biochemistry, Biophysics, and General Pathology, Second University of Naples, Naples, Italy; eUnit of Endocrinology and Diabetology, Bambino Gesù Children’s Hospital, Rome, Italy; fPediatric Endocrinology Unit, Department of Translational Medical Sciences, University ‘Federico II’ of Naples, Naples, Italy

Background: Children with familial forms of central diabetes insipidus (CDI) display polyuria and polydipsia within the first years of life.

Objective and hypotheses: We hypothesize that children with an early-onset idiopathic CDI might be affected by de novo genetic mutations.

Method: Eleven children aged between 1 month and 7 years with polyuria and polydipsia and negative family history were enrolled. In nine of them with CDI the arginine–vasopressin–neurophysin II (AVP-NPII) and Wolframin genes (WS1) were sequenced.

Results: Two patients carried a mutation in AVP-NPII gene: a heterozygous G to T transversion 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 residue at position 18 (p.Ser18del) of the AVP pre-prohormone signal peptide. A third patient carried two heterozygous mutations in the WFS1 gene, each localized on a different allele. The first change was A to G transition at nucleotide 997 in exon 8 (c.997A>G), resulting in the change of valine at position 333 in place of isoleucine (p.Ile333Val). The second novel mutation was a 3 bp insertion in exon 8, c.2392-2393insACG that gave origin to the addition of a third consecutive aspartic acid at position 797 and the maintenance of the correct open reading frame (p. Asp797_Val798insAsp). While no changes of WS1 protein level were evidenced in the fibroblasts from healthy individuals as well as from the patient and his parents, a major sensitivity to staurosporine-induced apoptosis was observed only in the fibroblasts of the patient, as demonstrated by increased poly(ADP-ribose polymerase) cleavage and caspase 3 activation.

Conclusion: Early-onset idiopathic CDI is associated with de novo mutations of AVP-NPII gene and with never reported hereditary changes of WFS1 gene. These findings have valuable implications for genetic counseling.