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Finding Genes in Leber Congenital Amaurosis

Maumenee I. H., Dhamaraj S., Yingying L.,
The Wilmer Eye Institute, Maumenee Building, Suite 517, Johns Hopkins Hospital (Baltimore)

Purpose: We undertook a study to identify the genes involved in Leber Congenital Amaurosis, since treatment for patients will depend upon understanding of the underlying genetic defect. Background: LCA affects 1:50,000 people. The phenotype is variable: the fundus may be normal, show "macular coloboma like" lesions, or be characterized by pigment migration; the acuities range from 20/100 to no light perception; the disease may be progressive or stable. Multiple permutations exist. Intuitively, the disease is heterogeneous and indeed, six causative genes have been identified to date, five of which lead to autosomal recessive disease; mutations in CRX are presumed to lead to autosomal dominant disease.
Material and methods: We collected 288 probands with LCA and established their pedigrees. Consanguinity was observed in 42, an additional 14 pedigrees were large potentially permitting identification coinheritance of the parental haplotypes with disease. Homozygosity mapping in these 56 pedigrees was performed using DNA from affected patients and their parents and markers spaced 25 cM apart. In subsequent runs adjacent markers and unaffected sibs were included. To date, positive linkage results were found in 54 pedigrees, in five instances in previously identified regions. Concurrently, mutation analysis was performed for known genes.
Results: 18 new loci were identified using information from pedigrees. The LOD scores vary from low positive to above 4, and the size of any given locus varies dependent upon number of families mapped to a given locus, degree of consanguinity, family size and number of available DNA samples.
Discussion: The number of loci - and hence genes - identified for LCA is very high given the rarity of the disease. The high frequency of consanguinity observed in our families is compatible with a model where the disease frequency results from the additive effect of monogenic homozygosity for a mutation in a number of rare genes.
Conclusions: There may be several reasons for the high gene frequency in the face of rarity of the disease: each involved gene is small and hence mutations are rare; we may be observing the mild end of the phenotypic spectrum of mutations leading to LCA, more severe mutations in the gene may be genetic lethals; di- or oligogenic inheritance may be the rule, leading to rare clinical manifestation, dependent upon tri- or oligoallelic inheritance. In two instances we observed heterozygous CRX mutations in patient and a phenotypically normal first degree relative; the significance of mutations in CRX as causative of LCA should be questioned. Six genes causing LCA have been identified to date; our data give evidence for 17 additional loci. It is estimated that a minimum of 30 genes are the cause of LCA, and therefore LCA in a population arises because of the additive effect of mono- or oligogenig inheritance of individually rare mutations in a large number of genes.