title: Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified.
abstract: Wolfram syndrome (WS) is a neuro-degenerative autosomal recessive (AR) disorder (OMIM #222300) caused by mutations in the WFS1 gene on 4p16.1. More than 120 mutations have been identified in WFS1 associated with AR WS, as well as autosomal dominant nonsyndromic low-frequency sensorineural hearing loss (LFSNHL). WFS1 variants were identified in eight subjects from seven families with WS, leading to the identification of four novel mutations, Q194X (nonsense), H313Y (missense), L313fsX360 (duplication frame shift) and F883fsX951 (deletion frame shift), and four previously reported mutations, A133T and L543R (missense), V415del (in frame triple deletion) and F883fsX950 (deletion frame shift). A mutation was found in 11/14 disease chromosomes, two subjects were homozygous for one mutation, one subject was compound heterozygous for two nucleotide substitutions (missense), one subject was compound heterozygous for a duplication and a deletion (frame shift), and in three families only one mutation was detected (Q194X and H313Y). All affected individuals shared clinically early-onset diabetes mellitus and progressive optic atrophy with onset in the first and second decades, respectively. In contrast, diabetes insipidus was present in two subjects only. Various degrees and types of hearing impairment were diagnosed in six individuals and cataract was observed in five subjects.
authors.affiliation: The Wilhelm Johannsen Centre for Functional Genome Research, Institute of Medical Biochemistry and Genetics, Panum Institute, University of Copenhagen, Copenhagen N, Denmark. larsh@medgen.ku.dk
authors.forename: Lars
authors.initials: L
authors.lastname: Hansen
authors.forename: Hans
authors.initials: H
authors.lastname: Eiberg
authors.forename: Timothy
authors.initials: T
authors.lastname: Barrett
authors.forename: Toke
authors.initials: T
authors.lastname: Bek
authors.forename: Per
authors.initials: P
authors.lastname: Kjaersgaard
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Tranebjaerg
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D003718:Denmark; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D014929:Wolfram Syndrome / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C114987:wolframin protein