title: Molecular detection of novel WFS1 mutations in patients with Wolfram syndrome by a DHPLC-based assay.
abstract: Wolfram syndrome (WS) is a recessively inherited mendelian form of diabetes and neurodegeneration also known by the acronym DIDMOAD from the major clinical features, including diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Affected individuals may also show renal tract abnormalities as well as multiple neurological and psychiatric symptoms. The causative gene for WS (WFS1) encoding wolframin maps to chromosome 4p16.1 and consists of eight exons, spanning 33.44 Kb of genomic DNA. In this study we report on the mutational analysis of the WFS1 coding region in 19 Italian WS patients and 25 relatives, using a DHPLC-based protocol. A total of 19 different mutations in WFS1 were found in 18 of 19 patients (95%). All these mutations, except one, are novel, preferentially located in WFS1 exon 8, and include deletions, insertions, duplications, and nonsense and missense changes. In particular, a 16 base-pair deletion in WFS1 codon 454 was detected in five different unrelated nuclear families, being the most prevalent alteration in this Italian group. Nine neutral changes and polymorphisms were also identified. Overall, this study represents the molecular characterization of the largest cohort of Italian WS patients and carriers studied so far, and increases the number of identified WFS1 allelic variants worldwide.
authors.affiliation: IRCCS-CSS, San Giovanni Rotondo and CSS-Mendel Institute, Rome, Italy. a.colosimo@css-mendel.it
authors.forename: Alessia
authors.initials: A
authors.lastname: Colosimo
authors.forename: Valentina
authors.initials: V
authors.lastname: Guida
authors.forename: Luciana
authors.initials: L
authors.lastname: Rigoli
authors.forename: Chiara
authors.initials: C
authors.lastname: Di Bella
authors.forename: Alessandro
authors.initials: A
authors.lastname: De Luca
authors.forename: Silvana
authors.initials: S
authors.lastname: Briuglia
authors.forename: Liborio
authors.initials: L
authors.lastname: Stuppia
authors.forename: Damiano Carmelo
authors.initials: DC
authors.lastname: Salpietro
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D002648:Child; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis / Q000379:methods*; D005091:Exons / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D007558:Italy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009691:Nucleic Acid Denaturation; D011110:Polymorphism, Genetic / Q000235:genetics; D014929:Wolfram Syndrome / Q000235:genetics* / Q000503:physiopathology
chemical_list: D008565:Membrane Proteins; C114987:wolframin protein