Abstract
Congenital cataracts are an important cause of bilateral visual impairment in infants. Through genome-wide linkage analysis in a four-generation family of Irish descent, the disease-associated gene causing autosomal-dominant congenital nuclear cataract was mapped to chromosome 4p16.1. The maximum logarithm of odds (LOD) score was 2.62 at a recombination fraction θ=0, obtained for marker D4S432 physically close to the Wolfram gene (WFS1). By sequencing the coding regions and intron–exon boundaries of WFS1, we identified a DNA substitution (c.1385A-to-G) in exon 8, causing a missense mutation at codon 462 (E462G) of the Wolframin protein. This is the first report of a mutation in this gene causing an isolated nuclear congenital cataract. These findings suggest that the membrane trafficking protein Wolframin may be important for supporting the developing lens.
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References
Reddy MA, Francis PA, Berry V, Bhattacharya SS, Moore AT : Molecular genetic basis of inherited cataract and associated phenotypes. Surv Ophthalmol 2004; 49: 300–315.
Krumpaszky HG, Klauss V : Epidemiology of blindness and eye disease. Ophthalmologica 1996; 210: 1–84.
Francis PJ, Berry V, Bhattacharya SS, Moore AT : The genetics of childhood cataract. J Med Genet 2000a; 37: 481–488.
Shiels A, Bennett TM, Hejtmancik JF : Cat-Map: putting cataract on the map. Mol Vis 2010; 16: 2007–2015.
Schmidt-Kastner R, Kreczmanski P, Preising M et al: Expression of the diabetes risk gene wolframin (WFS1) in the human retina. Exp Eye Res 2009; 89: 568–574.
Kawano J, Tanizawa Y, Shinoda K : Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system. J.Comp Neurol 2008; 510: 1–23.
Takeda K, Inoue H, Tanizawa Y, Matsuzaki Y et al: WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Hum Mol Genet 2001; 10: 477–484.
Hofmann S, Philbrook C, Gerbitz KD, Bauer MF : Wolfram syndrome: structural and functional analyses of mutant and wild-type Wolframin, the WFS1 gene product. Hum Mol Genet 2003; 12: 2003–2012.
Strom TM, Hörtnagel K, Hofmann S et al: Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (Wolframin) coding for a predicted transmembrane protein. Hum Mol Genet 1998; 7: 2021–2028.
Wolfram DJ, Wagener HP : Diabetes mellitus and simple optic atrophy among siblings: report of four cases. Mayo Clin Proc 1938; 13: 715–718.
Barrett TG, Bundey SE, Macleod AF : Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet 1995; 346: 1458–1463.
Cryns K, Sivakumaran TA, Van den Ouweland JM et al: Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease. Hum Mutation 2003; 22: 275–287.
Tranebjaerg L, Barrett T, Rendtorff ND : WFS1-related disorders. GeneReviews at GeneTests: Medical Genetics Information Resource. University of Washington: Seattle, 2009, pp 1997–2008.
Young TL, Ives E, Lynch E et al: Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1. Hum Mol Genet 2001; 10: 2509–2514.
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 2005; 12: 1275–1284.
Eiberg H, Hansen L, Kjer B et al: Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene. J Med Genet 2006; 43: 435–440.
Rendtorff ND, Lodahl M, Boulahbel H et al: Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment. Am J Med Genet A 2011; 6: 1298–1313.
Waschbisch A, Volbers B, Struffert T et al: Primary diagnosis of Wolfram syndrome in an adult patient-case report and description of a novel pathogenic mutation. J Neurol Sci 2011; 300: 191–193.
Rigoli L, Lombardo F, Di Bella C : Wolfram syndrome and WFS1 gene. Clin Genet 2011; 79: 103–117.
Pyati UJ, Gjini E, Carbonneau S et al: Look AT. p63 mediates an apoptotic response to pharmacological and disease-related ER stress in the developing epidermis. Dev Cell 2011; 21: 492–505.
Acknowledgements
This work was supported by The Wellcome Trust project grant 063969/Z/01, EU project ‘PYTHIA’ (FP7-ICT2–224030), and ‘the National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.’ We would like to thank the members of the family for taking part in this study.
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Electronic-database information, The accession number and URL for data in this article are as follows
Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/omim (for WFS1 (MIM 606201)) Marshfield, GDB Human genome database (http://research.marshfieldclinic.org) and ENSEMBLE genome data resources (http://www.ensembl.org).
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Berry, V., Gregory-Evans, C., Emmett, W. et al. Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans. Eur J Hum Genet 21, 1356–1360 (2013). https://doi.org/10.1038/ejhg.2013.52
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DOI: https://doi.org/10.1038/ejhg.2013.52
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