Novel mutations in the gamma-crystallin genes cause autosomal dominant congenital cataracts

Cataract is an opacification of the eye lens that frequently results in visual impairment or blindness during infancy and early childhood.1 An estimated 200 000 children are blind with bilateral cataract world wide and 20 000-40 000 children with developmental cataract are born each year.2 In the developed nations of Europe and Northern America, national surveillance or cross sectional studies suggest a prevalence of 1-4 cases per 10 000 children.3–6 In southern India the prevalence is higher, at approximately 6.5 cases per 10 000 children7 and bilateral childhood cataract accounts for about 12% of all ocular disorders registered.8 The lens is a unique tissue as it is separated from the surrounding fluids by the lens capsule and there is life long persistence of its cells and their proteins. The β- and γ-crystallins were biochemically characterised as major lens proteins by Morner9 over a century ago. They belong to a superfamily of proteins, which were considered for a long time to be present only in the lens. However, it has recently been reported that β- and γ-crystallin mRNA and protein are also present in other tissues, in particular in the retina, brain, and testis.10–12 The common signature of all β- and γ-crystallins is the so called Greek key motif. Crystallography has shown that each of the β- and γ-crystallins is composed of two domains, each built up by two Greek key motifs. It is widely accepted that β/γ-crystallins evolved in two duplication steps from an ancestral gene coding for a protein folded like a Greek key. The γ-crystallin encoding genes ( Cryg / CRYG genes) in all mammals consist of three exons: the first one codes only for three amino acids, and the subsequent two are responsible for two Greek key motifs each. …