Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL.
Leber congenital amaurosis (LCA) is a congenital retinal dystrophy characterized by severe visual loss in infancy and nystagmus. Although most often inherited in an autosomal recessive fashion, rare individuals with mutations in the cone-rod homeobox gene, CRX, have dominant disease. CRX is critical for photoreceptor development and acts synergistically with the leucine-zipper transcription factor, NRL. We report on the phenotype of two individuals with LCA due to novel, de novo CRX mutations, c.G264T(p.K74N) and c.413delT(p.I138fs48), that reduce transactivation in vitro to 10% and 30% of control values, respectively. Whereas the c.413delT(p.I138fs48) mutant allows co-expressed NRL to transactivate independently at its normal, baseline level, the c.G264T(p.K74N) mutant reduces co-expressed NRL transactivation and reduces steady state levels of both proteins. Although both mutant proteins predominantly localize normally to the nucleus, they also both show variable cytoplasmic localization. These observations suggest that some CRX-mediated LCA may result from effects beyond haploinsufficiency, such as the mutant protein interefering with other transcription factors' function. Such patients would therefore not likely benefit from a simple, gene-replacement strategy for their disease.
Nichols
Lorenzo L
LL
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Alur
Ramakrishna P
RP
Boobalan
Elangovan
E
Sergeev
Yuri V
YV
Caruso
Rafael C
RC
Stone
Edwin M
EM
Swaroop
Anand
A
Johnson
Mary A
MA
Brooks
Brian P
BP
D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005799:Genes, Dominant; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D050976:Basic-Leucine Zipper Transcription Factors; D005136:Eye Proteins; D018398:Homeodomain Proteins; C490037:NRL protein, human; D015534:Trans-Activators; C109288:cone rod homeobox protein