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Human Molecular Genetics Advance Access originally published online on June 30, 2004
Human Molecular Genetics 2004 13(17):1893-1902; doi:10.1093/hmg/ddh198
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Human Molecular Genetics, Vol. 13, No. 17 © Oxford University Press 2004; all rights reserved

Nuclear receptor NR2E3 gene mutations distort human retinal laminar architecture and cause an unusual degeneration

Samuel G. Jacobson1,*, Alexander Sumaroka1, Tomas S. Aleman1, Artur V. Cideciyan1, Sharon B. Schwartz1, Alejandro J. Roman1, Roderick R. McInnes2, Val C. Sheffield3,4, Edwin M. Stone3,4, Anand Swaroop5,6,7 and Alan F. Wright8

1Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA, 2Programs in Development and Genetics, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8, 3Department of Pediatrics and 4Department of Ophthalmology, Howard Hughes Medical Institute, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA, 5Department of Ophthalmology, 6Department of Visual Sciences and 7Department of Human Genetics, University of Michigan, Ann Arbor, MI 48105, USA and 8MRC Human Genetics Unit, Western General Hospital, Edinburgh, Scotland

Received April 19, 2004; Accepted June 15, 2004

Mutations in the nuclear receptor gene, NR2E3, cause a disorder of human retinal photoreceptor development characterized by hyperfunction and excess of the minority S (short wavelength or blue) cone photoreceptor type, but near absence of function of the majority rod receptor. NR2E3 disease can also progress to blindness. How the human retina accommodates mis-specified types and numbers of neurons and advances to retinal degeneration are unknown. We studied the retinal organization in vivo of patients with NR2E3 mutations. Early human NR2E3 disease with S cone hyperfunction showed thickened retinal layers within an otherwise normally structured retina. With visual loss, however, lamination was coarse and there was a strikingly thick and bulging appearance to the retina, localized to an annulus encircling the central fovea. This pattern was not found in other retinal degenerations. The abnormal laminar retinal architecture of early NR2E3 disease may be due in part to larger cells with an S cone phenotype in place of rods that failed to differentiate. The later-stage dysplastic appearance suggests a previously unrecognized proliferative response in human retinal degeneration.

* To whom correspondence should be addressed at: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, 51 N. 39th Street, Philadelphia, PA 19104, USA. Tel: +1 2156629981; Fax: +1 2156629388; Email: jacobsos{at}mail.med.upenn.edu


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