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.
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Acknowledgements
The excellent technical assistance in this work was carried out by Lillian Rasmussen, Annemette Mikkelsen and Mona Kristensen, the patients and relatives are thanked for their patience and collaboration. We also thank Henning Laursen, neuro-pathologist at The University Hospital, Rigshospitalet, Copenhagen, for commenting on the autopsia report. The project was hosted by the Wilhelm Johannsen Centre for Functional Genomics and GENOME GROUP/RC-LINK, and supported by a grant from The Danish Society of the Blind, the Oticon Foundation and Widex AS. The Danish National Research Foundation funded The Wilhelm Johannsen Centre for Functional Genomics.
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Hansen, L., Eiberg, H., Barrett, T. et al. Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified. Eur J Hum Genet 13, 1275–1284 (2005). https://doi.org/10.1038/sj.ejhg.5201491
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DOI: https://doi.org/10.1038/sj.ejhg.5201491
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