title: Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration.
abstract: 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.
authors.affiliation: Department of Ophthalmology, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Friedman
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: Chitra
authors.initials: C
authors.lastname: Kannabiran
authors.forename: Christina
authors.initials: C
authors.lastname: Chakarova
authors.forename: Hardeep P
authors.initials: HP
authors.lastname: Singh
authors.forename: Subhadra
authors.initials: S
authors.lastname: Jalali
authors.forename: Norman L
authors.initials: NL
authors.lastname: Hawes
authors.forename: Kari
authors.initials: K
authors.lastname: Branham
authors.forename: Mohammad
authors.initials: M
authors.lastname: Othman
authors.forename: Elena
authors.initials: E
authors.lastname: Filippova
authors.forename: Debra A
authors.initials: DA
authors.lastname: Thompson
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.forename: Sten
authors.initials: S
authors.lastname: Andréasson
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Shomi S
authors.initials: SS
authors.lastname: Bhattacharya
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
mesh_terms: 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
chemical_list: D009687:Nuclear Proteins; C516799:retinal degeneration 3 protein, mouse