Copyright © 2006 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 79, Issue 6, 1059-1070, 1 December 2006
doi:10.1086/510021
Article
Premature Truncation of a Novel Protein, RD3, Exhibiting Subnuclear Localization Is Associated with Retinal Degeneration
James S. Friedmana, Bo Changc, Chitra Kannabirand, Christina Chakarovaf, Hardeep P. Singhd, Subhadra Jalalie, Norman L. Hawesc, Kari Branhama, Mohammad Othmana, Elena Filippovaa, Debra A. Thompsona, Andrew R. Websterf, g, Sten Andréassonh, Samuel G. Jacobsoni, Shomi S. Bhattacharyaf, John R. Heckenlively and Anand Swaroopb, 
, 
a From the Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor
b Department of Human Genetics, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor
c the Jackson Laboratory, Bar Harbor, Maine
d Kallam Anji Reddy Molecular Genetics Laboratory, L. V. Prasad Eye Institute, Banjara Hills, Hyderaba, India
e Kannuri Santhamma Retina-Vitreous Services, L. V. Prasad Eye Institute, Banjara Hills, Hyderaba, India
f Department of Molecular Genetics, Institute of Ophthalmology, University College London, London
g Moorfield Eye Hospital, London
h Department of Ophthalmology, University Hospital of Lund, Lund, Sweden
i Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia
Address for correspondence and reprints: Dr. Anand Swaroop, W. K. Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105Abstract
The rd3 mouse is one of the oldest identified models of early-onset retinal degeneration. Using the positional candidate approach, we have identified a C→T substitution in a novel gene, Rd3, that encodes an evolutionarily conserved protein of 195 amino acids. The rd3 mutation results in a predicted stop codon after residue 106. This change is observed in four rd3 lines derived from the original collected mice but not in the nine wild-type mouse strains that were examined. Rd3 is preferentially expressed in the retina and exhibits increasing expression through early postnatal development. In transiently transfected COS-1 cells, the RD3-fusion protein shows subnuclear localization adjacent to promyelocytic leukemia-gene-product bodies. The truncated mutant RD3 protein is detectable in COS-1 cells but appears to get degraded rapidly. To explore potential association of the human RD3 gene at chromosome 1q32 with retinopathies, we performed a mutation screen of 881 probands from North America, India, and Europe. In addition to several alterations of uncertain significance, we identified a homozygous alteration in the invariant G nucleotide of the RD3 exon 2 donor splice site in two siblings with Leber congenital amaurosis. This mutation is predicted to result in premature truncation of the RD3 protein, segregates with the disease, and is not detected in 121 ethnically matched control individuals. We suggest that the retinopathy-associated RD3 protein is part of subnuclear protein complexes involved in diverse processes, such as transcription and splicing.
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