ESPE Abstracts (2014) 82 P-D-1-3-185

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.

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