Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans

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.

Figure 1

Abridged pedigree of the nuclear cataract family used in this study showing the segregation of five chromosome 4p markers listed in descending order. Squares and circles symbolize males and females, respectively. Open and filled symbols indicate unaffected and affected individuals. The disease haplotype is shown in the box.

Figure 2

Sequence analysis of WFS1 with unaffected individual (upper chromatogram illustrates a normal control) and a missense mutation (c.1385A-to-G; shown in an affected individual).

Figure 3

Expression of Wfs1 in the developing mouse eye. Left panel (a): western blot for Wfs1 protein. Lane1, whole-eye extract at E18.5; Lane 2, lens extract at P3, Lane3, lens extract at P21. M, GenScript protein marker. Antibody to GAPDH used as loading control. Right panels (b and c): upper images are sectioned stained without primary antibody; middle images are immunolabelling of Wfs1 (white arrows) in the developing mouse eye; lower images are H&E wax sections showing corresponding eye histology. L, lens; R, retina; E, eyelid.