Showing papers by "Anand Swaroop published in 1999"

Leber Congenital Amaurosis Caused by a Homozygous Mutation (R90W) in the Homeodomain of the Retinal Transcription Factor CRX: Direct Evidence for the Involvement of CRX in the Development of Photoreceptor Function

Abstract: The CRX (cone-rod homeobox) gene is specifically expressed in developing and mature photoreceptors and encodes an otd/Otx-like paired homeodomain protein. Mutant alleles of the CRX gene have recently been associated with autosomal dominant cone-rod dystrophy (CORD) as well as dominant Leber congenital amaurosis (LCA). Since LCA is more commonly inherited in an autosomal recessive manner, we examined a cohort of recessive LCA patients for CRX mutations. A homozygous substitution of arginine (R) at codon 90 by tryptophan (W) was identified in the CRX homeodomain of one of the probands who was nearly blind from birth. A group of 48 control individuals and 190 previously characterized CORD probands did not reveal this sequence change. The mutant CRX R90W homeodomain demonstrated decreased binding to the previously identified cis sequence elements in the rhodopsin promoter. In transient transfection experiments, the mutant protein showed significantly reduced ability to transactivate the rhodopsin promoter, as well as lower synergistic activation with the bZIP transcription factor NRL. Heterozygosity of the mutant CRX (R90W) allele was detected in both parents and in an older sibling. Ophthalmologic examination and electroretinography revealed a subtle abnormality of cone function in both the parents. These data suggest that the R90W mutation results in a CRX protein with reduced DNA binding and transcriptional regulatory activity and that the subsequent changes in photoreceptor gene expression lead to the very early onset severe visual impairment in LCA.

Protein-truncation mutations in the RP2 gene in a North American cohort of families with X-linked retinitis pigmentosa.

Abstract: We thank Drs. Sten Andreasson, David Birch, Nancy Carson, Bernie Chodirker, Mark Evans, Gerald Fishman, John Heckenlively, Dennis Hoffman, Maria Musarella, and Beth Spriggs and Mr. Eric L. Krivchenia for some of the patient samples that were included in the mutation screening. We acknowledge the assistance of Dr. Wolfgang Berger for providing the RP2 primer sequences. We thank Dr. Monika Buraczynska for organization of the patient registry; Dr. Radha Ayyagari for discussions; Dr. Beverly Yashar for counseling; Ms. Cara Coats for assistance in patient collection; Mr. Jason Cook, Ms. Patricia Forsythe, and Ms. Eve Bingham for technical assistance; and Ms. D. Giebel for secretarial assistance. This research was supported by National Institutes of Health (NIH) grants EY05627, EY06094, and EY07961 and by grants from the Foundation Fighting Blindness, the Chatlos Foundation, the Kirby Foundation, the Mackall Trust, and Research to Prevent Blindness. We also acknowledge NIH grants EY07003 (core) and M01-RR00042 (General Clinical Research Center) and a shared equipment grant from the Office of Vice President for Research (University of Michigan). A.S. is recipient of a Lew R. Wasserman Merit Award, and P.A.S., a Senior Scientific Investigator Award, both from Research to Prevent Blindness.

What can we learn about age-related macular degeneration from other retinal diseases?

Abstract: Age-related macular degeneration (AMD) is increasingly recognized as a complex genetic disorder in which one or more genes contribute to an individual's susceptibility for developing the condition. Twin and family studies as well as population-based genetic epidemiologic methods have convincingly demonstrated the importance of genetics in AMD, though the extent of heritability, the number of genes involved, and the phenotypic and genetic heterogeneity of the condition remain unresolved. The extent to which other hereditary macular dystrophies such as Stargardts disease, familial radial drusen (malattia leventinese), Best's disease, and peripherin/RDS-related dystrophy are related to AMD remains unclear. Alzheimer's disease, another late onset, heterogeneous degenerative disorder of the central nervous system, offers a valuable model for identifying the issues that confront AMD genetics.