Defect of LSS Disrupts Lens Development in Cataractogenesis

An estimated 95 million people worldwide are affected by cataract. Cataract still remains the leading cause of blindness in middle-income and low-income countries. With the advancement of surgical technology and techniques, cataract surgery has evolved to small-incisional surgery with rapid visual recovery, good visual outcomes, and minimal complications in most patients. With the development of advanced technology in intraocular lenses, the combined treatment of cataract and astigmatism or presbyopia, or both, is possible. Paediatric cataracts have a different pathogenesis, surgical concerns, and postoperative clinical course from those of age-related cataracts, and the visual outcome is multifactorial and dependent on postoperative visual rehabilitation. New developments in cataract surgery will continue to improve the visual, anatomical, and patient-reported outcomes. Future work should focus on promoting the accessibility and quality of cataract surgery in developing countries.

Cataract can be defined as any opacity of the crystalline lens. Congenital cataract is particularly serious because it has the potential for inhibiting visual development, resulting in permanent blindness. Inherited cataracts represent a major contribution to congenital cataracts, especially in developed countries. While cataract represents a common end stage of mutations in a potentially large number of genes acting through varied mechanisms in practice most inherited cataracts have been associated with a subgroup of genes encoding proteins of particular importance for the maintenance of lens transparency and homeostasis. The increasing availability of more detailed information about these proteins and their functions and is making it possible to understand the pathophysiology of cataracts and the biology of the lens in general.

The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.