title: Molecular characterization of WFS1 in an Iranian family with Wolfram syndrome reveals a novel frameshift mutation associated with early symptoms.
abstract: Wolfram syndrome (WS) is a rare autosomal recessive neurodegenerative disorder that represents a likely source of childhood diabetes especially among countries in the consanguinity belt. The main responsible gene is WFS1 for which over one hundred mutations have been reported from different ethnic groups. The aim of this study was to identify the molecular etiology of WS and to perform a possible genotype-phenotype correlation in Iranian kindred. An Iranian family with two patients was clinically studied and WS was suspected. Genetic linkage analysis via 5 STR markers was carried out. For identification of mutations, DNA sequencing of WFS1 including all the exons, exon-intron boundaries and the promoter was performed. Linkage analysis indicated linkage to the WFS1 region. After DNA sequencing of WFS1, one novel pathogenic mutation, which causes frameshift alteration c.2177_2178insTCTTC (or c.2173_2177dupTCTTC) in exon eight, was found. The genotype-phenotype correlation analysis suggests that the presence of the homozygous mutation may be associated with early onset of disease symptoms. This study stresses the necessity of considering the molecular analysis of WFS1 in childhood diabetes with some symptoms of WS.
authors.affiliation: Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Sobhani
authors.forename: Mohammad Amin
authors.initials: MA
authors.lastname: Tabatabaiefar
authors.forename: Asadollah
authors.initials: A
authors.lastname: Rajab
authors.forename: Abdol-Mohammad
authors.initials: AM
authors.lastname: Kajbafzadeh
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Noori-Daloii
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D008040:Genetic Linkage; D006801:Humans; D007492:Iran; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D010375:Pedigree; D014929:Wolfram Syndrome / Q000235:genetics*; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C114987:wolframin protein
keywords: BLAST; Basic Local Alignment Search Tool; DI; DI-DM-OA-D; DM; DNA; Dup; EDTA; FVC; Genetic linkage analysis; Iran; LOD; NCBI; National Center for Biotechnology Information; Novel mutation; OA; PAGE; PCR; SLINK; STR; VCUG; WFS1; WS; Wolfram syndrome; Wolfram syndrome 1 gene; aa; amino acid; dNTP; ddH2O; deoxyribonucleic acid; deoxyribonucleotide triphosphate; diabetes insipidus; diabetes insipidus, diabetes mellitus, optic atrophy and deafness; diabetes mellitus; double-distilled dihydrogen monoxide/water; duplication; ethylenediaminetetraacetic acid; frequency volume chart; logarithm of odds; optic atrophy; polyacrylamide gel electrophoresis; polymerase chain reaction; short tandem repeats; simulation of linkage; voiding cystourethrogram