C ataract, or opacification of all or part of the lens of the eye, reduces optical performance, most commonly manifested by decreased visual acuity, glare and decreased contrast sensitivity. While age-related cataract is the commonest cause of visual impairment world-wide 1 , most advances have been made in understanding the genetic basis of its congenital counterpart. Congenital cataract is the commonest treatable cause of childhood blindness in Europe and the USA with a preva- lence of 1.8 cases per 10 000 (Ref. 2). Presentation is most usual in early infancy, with static or slowly progressive lens opacities that are usually bilateral and symmetrical. The level of irreversible visual compromise that arises without appropriate management depends upon the position of the opacity within the lens and the degree of opacification 3 . Inherited cataract accounts for around half of all con- genital cataract 4 and is a recognized feature of almost 200 genetic diseases 5 , including galactosaemia, Nance–Horan and Down syndromes. In most instances, however, cataract is inherited non-syndromically as an isolated abnormality. In non-consanguinous populations, the majority of inherited cataract shows autosomal dominant inheritance. Many apparently sporadic congenital cataracts might also have a genetic basis 4 . The first description of a family with inherited cataract was published by Nettleship and Ogilvie in 1906 (Ref. 6). Later, Nettleship described a genealogically distinct family with a similar phenotype. This family was re-investigated in 1963, and the disease shown to co-segregate with the Duffy blood group locus 7 . This became the first human autosomal disease to be genetically linked when in 1968, the Duffy locus was assigned to chromosome 1 (Ref. 8). Lens morphogenesis Studies of lens embryology and gene expression have made important contributions to our current understand- ing of the developmental periods during which the lens is susceptible to adverse influences, thus helping to explain the observed spatial and temporal patterns of cataract. In the human, lens organogenesis (Fig. 1) begins in the 4 mm embryo (fourth week of gestation) with thickening of the surface ectoderm overlying the optic vesicle to form the epithelial cells of the lens placode 9 . Invagination of this area produces the lens pit, which closes over to form the lens vesicle. A temporary connection with the surface ectoderm is retained (the lens stalk). Cells lining the posterior wall lose their nuclei and rapidly elongate, obliterating the cavity of the vesicle to form primary lens fibres. Secondary lens fibres are subse- quently produced throughout life by division of anterior lens epithelial cells in the equatorial zone of the lens and form lamellae, compacting more central fibres 10 . Mature lens fibres do not divide and there is minimal turnover of their protein constituents. Points at which secondary lens fibres come into apposition result in lines of optical discontinu- ity or ‘sutures’ 11 . The lens is surrounded by a capsule of mesenchymal origin. Successful organogenesis results in a transparent biconvex lens suspended in the eye by zonular ligaments, between the aqueous humour and the vitreous body. Exchange of waste products and nutrients occurs with the aqueous humour across the semi-permeable lens capsule 12 . Secondary lens fibre formation does not result in opti- cal homogeneity. Instead, concentric zones of varying refractive index develop, whose interfaces can be clearly delineated. The zones correspond to different developmen- tal stages, although controversy remains about their pre- cise nature. A nomenclature that best reflects the cataract phenotypes observed, and one that has a biochemical and histological basis, proposes that the lens consists of two parts: the nucleus, which is the total lens at birth, comprising embryonic and fetal parts, and the cortex that is laid down after birth 13 . Molecular and cell biology of lens development The lens forms through a temporally and spatially regu- lated pattern of differentiation, coordinated by several growth factors, for example fibroblast growth factors FGF1, -2, -3 and activin, and transcription factors such as PAX6, SIX3, SIX5 and PITX3. The roles of OPTX2 and retinoic acid in transcriptional regulation are less well established. In turn, the presence of the developing lens appears to be crucial for the normal development of other ocular structures. Reviews Lens biology: development and human cataractogenesis TIG May 1999, volume 15, No. 5 0168-9525/99/$ – see front matter © 1999 Elsevier Science All rights reserved. PII: S0168-9525(99)01738-2 Peter J. Francis* p.j.francis@hgmp.mrc. ac.uk Vanita Berry § vberry@hgmp.mrc. ac.uk Anthony T. Moore ‡ atm22@hermes.cam. ac.uk Shomi Bhattacharya ¶ smbcssb@ucl.ac.uk *Department of Molecular Genetics, Institute of Ophthalmology, University College London, 11–43 Bath Street, London, UK EC1V 9EL; and Moorfields Eye Hospital, 162 City Road, London, UK EC1V 2PD. § Department of Molecular Genetics, Institute of Ophthalmology, University College London, 11–43 Bath Street, London, UK EC1V 9EL. ‡ Consultant Ophthalmologist, Moorfields Eye Hospital, 162 City Road, London, UK EV1V 2PD; and Addenbrooke’s Hospital, Hills Road, Cambridge, UK CB2 2QQ. ¶ Department of Molecular Genetics, Institute of Ophthalmology, University College London, 11–43 Bath Street, London, UK EC1V 9EL. 191 Cataract, or opacification of the lens of the eye, is the commonest cause of visual impairment world-wide. It is only treatable at present by surgical removal. Recent advances in our understanding of the genetics of human cataract, in particular the inherited congenital form, together with the development of an array of animal models have provided valuable new insights into normal vertebrate lens biology and the mechanisms that underlie cataract formation. In this article, we review the current state of research in these areas and discuss thinking regarding the relationship between the phenotypes observed and the underlying genotype in inherited cataract. Lens biology development and human cataractogenesis