title: A new structural rearrangement associated to Wolfram syndrome in a child with a partial phenotype.
abstract: Wolfram syndrome (WS) is a rare autosomal recessive disorder characterized by diabetes insipidus (DI), insulin-dependent diabetes mellitus (DM), optic atrophy (OA) and deafness caused by mutations in WFS1 gene (4p16.1), which encodes an endoplasmic reticulum protein, called Wolframin. We describe the case of an infant who presented hypernatremia and severe hypoplasia of the left eyeball with alteration of visual evoked potentials. Persistent hypernatremia, iposmolar polyuria and high plasma osmolality suggested DI, confirmed by a normal urine concentration after vasopressin test. Treatment with vasopressin allowed a normalization of sodium levels and urine output. Brain magnetic resonance imaging showed absence of the neurohypophysis hyperintense signal, normal adenohypophysis and optic tracts hypoplasia. The concomitant presence of DI and OA, even in the absence of DM and deafness, prompted the suspicion of WS and complete genetic analysis was performed. Genomic DNA sequencing of WFS1 showed no inactivating mutations described to date, but suggested a structural mutation as markers genotyping revealed a segmental paternal heterodisomy involving the upstream regulatory region (promoter and 5'UTR). cDNA sequencing revealed the coexistence of the wild-type transcript and two splice variants; one variant, probably benign, is known in literature and the other one causes the loss of exon 2, containing the translation initiation site. Western blot confirmed a marked protein reduction. During the clinical follow-up child's condition remained stable and glucose metabolism is still in the standard. In conclusion, the phenotype associated with this structural rearrangement, which substantially reduces the synthesis of Wolframin, confirms a tissue-specific pattern of expression of WFS1, suggests the presence of a different protein dosage sensitivity in different tissues and could be causative of DI and OA in our patient. The "incomplete" phenotype here described, usually absent in typical WS cases, is explained by the residual Wolframin expression that would preserve other organs, i.e. pancreatic islets. A careful longitudinal clinical follow-up will assess any changes in the phenotypic penetrance in our patient.
authors: Endocrine Unit, Department of Clinical Sciences and Community Health,Università degli Studi di Milano, Fondazione IRCCS Cà-Granda Ospedale Maggiore Policlinico, Milan, 20122, Italy.
authors: Francesca M
authors: FM
authors: Elli
authors: Stefano
authors: S
authors: Ghirardello
authors: Claudia
authors: C
authors: Giavoli
authors: Silvana
authors: S
authors: Gangi
authors: Laura
authors: L
authors: Dioni
authors: Milena
authors: M
authors: Crippa
authors: Palma
authors: P
authors: Finelli
authors: Silvia
authors: S
authors: Bergamaschi
authors: Fabio
authors: F
authors: Mosca
authors: Anna
authors: A
authors: Spada
authors: Paolo
authors: P
authors: Beck-Peccoz
mesh_terms: D017398:Alternative Splicing; D001483:Base Sequence; D002675:Child, Preschool; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D004252:DNA Mutational Analysis; D015321:Gene Rearrangement; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D019683:Penetrance; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution; D024182:Uniparental Disomy / Q000235:genetics; D014929:Wolfram Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; C114987:wolframin protein