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We summarize 18 mutations in the human CRX gene that have been associated with Leber congenital amaurosis (congenital retinal blindness), cone-rod degeneration, or retinitis pigmentosa. Except for one obviously null allele not definitely associated with a phenotype (a frameshift in codon 9), all CRX mutations appear to be completely penetrant and cause disease in heterozygotes. These dominant alleles fall into two categories. In one group are missense mutations and short, in-frame deletions; in the second group are frameshift mutations, all of which are in the last exon. All of these dominant mutations are likely to produce stable mRNA that is translated. Mutations in the missense group preferentially affect the conserved homeobox (codons 39-98), and all frameshift mutations leave the homeodomain intact but alter the OTX motif encoded by codons 284-295 at the carboxy terminus. We could not uncover any correlation between type of disease (congenital amaurosis vs. cone-rod degeneration or retinitis pigmentosa) and the type of mutation (missense vs. frameshift). Four of the 18 mutations (approximately 20%) were de novo mutations, and all of these were found in isolate cases of Leber congenital amaurosis. Dominant CRX mutations have not been associated with mental retardation or developmental delay that has sometimes been found in Leber congenital amaurosis caused by other genes. Implications regarding potential future therapies are discussed.
