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Finding Genes in Leber Congenital
Maumenee I. H., Dhamaraj S., Yingying L.,
The Wilmer Eye Institute, Maumenee Building, Suite 517, Johns Hopkins
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
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.