EPOS

European Paediatric Ophthalmological Society

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38 Developmental genetics in ophthalmology and its impact on paediatric ophthalmology.

Graw, J.
GSF-National Research Center for Environment and Health, Institute of Mammalian Genetics

Much of our knowledge on the function of genes in mammalian development derived from the molecular analysis of spontaneous or induced mutations. Mutations affecting the eye can be easily identified, and, therefore, a remarkable number of such mutants have been investigated. Together with further mutants described in the literature, a mosaic can be built up reflecting important steps during lens development and differentiation.

To understand the mechanisms of eye development in detail, the isolation of the corresponding genes and the characterization of the mutations at the molecular level are important. A prerequisite for the molecular analysis is the chromosomal localization of the gene. Mutations, which are involved in eye development and mapped at a particular chromosome will be discussed according to the embryological time scale, reflecting also the genetic hierarchy of the genes:

• In the aphakia mouse mutant, two deletions in the promoter of the homeobox transcription factor Pitx3 lead to a loss of its function and to an arrest of eye development at the lens stalk stage. Mutations in the human PITX3 gene have been demonstrated by others to be causative for dysmorphology of the anterior segment of the eye and cataracts.

• The two Cat3 alleles in the mouse show alterations in the lens development at the transition from primary to secondary lens fiber cells. Finally, vacuolated lenses and synechies between lens, iris and cornea are observed. The mutations in the mouse maps very close to the locus for keratokan; mutations in the corresponding human KERA gene have been demonstrated by others to be causative for cornea plana congenita.

• Mutations in the g-crystallin encoding genes are the most frequent cause for congenital cataracts in the mouse. Indications from our first studies in congenital human cataracts support this point of view. Since the g-crystallins are expressed solely in the lens, no effect on other organs have to be expected.

• Some postnatal, progressive cataracts have been characterized by mutations in b-crystallin encoding genes. Since at least one of them is also expressed in the retina and the brain, effects on these tissues have to be considered, too.

The analysis of the genes and their mutations enables us to describe precisely the mechanisms leading to pathological situations. This analysis will help pediatrics in their assessment of the consequences of the disease for the patients and for their search for an adequate therapy. Therefore, the detailed genetic, biochemical and morphological analysis of mouse mutants is indispensible.