Cataract mutations and lens development.

Abstract

The lens plays an essential role for proper eye development. Mouse mutants affecting lens development are excellent models for corresponding human disorders. Moreover, using mutations in particular genes the process of eye and lens development can be dissected into distinct steps. Therefore, three mouse mutants will be described in detail and discussed affecting three essential stages: formation of the lens vesicle, initiation of secondary lens fiber cell formation, and terminal differentiation of the secondary fiber cells. The mutant aphakia (ak) has been characterized by bilaterally apakic eyes [Varnum and Stevens (1968) J. Hered. 59, 147-150], and the corresponding gene was mapped to chromosome 19 [Varnum and Stevens (1975) Mouse News Letters 53, 35]. Recent investigations in our laboratory refined the linkage 0.6 +/- 0.3 N cm proximal to the microsatellite marker D19Mit10. The linked gene Pax2, responsible for proper development of the posterior part of the eye and the optic nerve, was excluded as candidate gene by sequence analysis. Histological analysis of the homozygous ak mutants revealed a persisting lens stalk and subsequently the formation of lens rudiments. The lens defects led to irregular iris development and retinal folding. Congenital aphakia is known as a rare human anomaly. Besides a corneal dystrophy (CDTB), no corresponding disease is localized at the homologous region of human chromosome 10q23. The Cat3 mutations are characterized by vacuolated lenses caused by alterations in the beginning of secondary lens fiber cell differentiation at embryonic day 12.5. Secondary malformations develop at the cornea and the iris, but the retina remains unaffected. Two mutant alleles of the Cat3 locus have been mapped to mouse chromosome 10 very close to the microsatellite markers D10Mit41 and D10Mit95 (less than 0.3 cM). Since Cat3 is mapped to a position, which is homologous to human chromosome 12q21-24, the disorder cornea plana congenita can be considered as a candidate disease. The series of Cat2 mutations have been mapped close to the locus encoding the gamma-crystallin gene cluster Cryg [Löster et al. (1994) Genomics 23, 240-242]. The Cat2nop mutation is characterized by a deletion of 11 bp and an insertion of 4 bp in the 3rd exon of Crygh leading to a truncated gamma B-crystallin. The defect in the Crygh gene is causative for the stop of lens fiber cell differentiation from embryonic day 15.5 onward. Besides the lens, no further ocular tissue is affected. The Cat2 mouse mutants are interesting models for human cataracts caused by mutations in the gamma-crystallin genes at human chromosome 2q32-35. The ak, Cat3 and Cat2 mutants are discussed in the context of other mutants affecting early eye and lens development. Additionally, human congenital cataracts are discussed, which have been characterized similar to the mouse models. The overview of the three types of mutants demonstrates that genes, which affect the early eye development, e.g. at the lens vesicle stage, have consequences for the development of the whole eye. In contrast, if the mutation influences later steps of lens differentiation, the consequences are restricted to the lens only. These data indicate a decreasing effect of the lens for the regulation of eye development during embryogenesis.