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(Investigative Ophthalmology and Visual Science. 2000;41:2076-2079.)
© 2000 by The Association for Research in Vision and Ophthalmology, Inc.

A CRX Null Mutation Is Associated with Both Leber Congenital Amaurosis and a Normal Ocular Phenotype

Eduardo Silva1,2, Jun-Ming Yang1, Yingying Li2, Sharola Dharmaraj2, Olof H. Sundin1 and Irene H. Maumenee2

1 From the Molecular and Developmental Biology Laboratory, Department of Ophthalmology, Johns Hopkins University School of Medicine; and 2 Johns Hopkins Center for Hereditary Eye Diseases, Wilmer Ophthalmological Institute, Baltimore, Maryland.

PURPOSE. To identify and characterize new cone rod homeobox (CRX) mutations associated with the Leber congenital amaurosis phenotype.

METHODS. The human CRX gene was sequenced in 74 consecutive patients carrying the diagnosis of Leber congenital amaurosis.

RESULTS. Two mutations were identified in CRX that cause frameshifts and predict severe truncations of the encoded protein. One of these, a 1-bp insertion, spares only nine N-terminal amino acids, removing the homeodomain, WSP motif, and conserved OTX domain at the C terminus. Of the CRX mutations described in the literature, this is the first that convincingly represents a null allele of the gene. Although the patient heterozygous for this null allele is affected with Leber congenital amaurosis, it was surprising that her father, who had normal vision, was heterozygous for the same mutation.

CONCLUSIONS. These results strongly suggest that haploinsufficiency of CRX is not sufficient to cause a retinal disorder. Loss of function alleles of CRX appear to cause Leber congenital amaurosis through a recessive or multigenic mechanism.




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