Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration.
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.
Friedman
James S
JS
Department of Ophthalmology, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA.
Chang
Bo
B
Kannabiran
Chitra
C
Chakarova
Christina
C
Singh
Hardeep P
HP
Jalali
Subhadra
S
Hawes
Norman L
NL
Branham
Kari
K
Othman
Mohammad
M
Filippova
Elena
E
Thompson
Debra A
DA
Webster
Andrew R
AR
Andréasson
Sten
S
Jacobson
Samuel G
SG
Bhattacharya
Shomi S
SS
Heckenlively
John R
JR
Swaroop
Anand
A
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells / Q000378:metabolism; D016022:Case-Control Studies; D022003:Cell Nucleus Structures / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005060:Europe; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007194:India; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D009656:North America; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics*; D012164:Retinal Diseases / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D009687:Nuclear Proteins; C516799:retinal degeneration 3 protein, mouse