Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL

Lorenzo L Nichols II; Ramakrishna P Alur; Elangovan Boobalan; Yuri V Sergeev; Rafael C Caruso; Edwin M Stone; Anand Swaroop; Mary A Johnson; Brian P Brooks

doi:10.1002/humu.21268

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Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL

Journal article

Open access

Peer reviewed

Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL

Lorenzo L Nichols II, Ramakrishna P Alur, Elangovan Boobalan, Yuri V Sergeev, Rafael C Caruso, Edwin M Stone, Anand Swaroop, Mary A Johnson and Brian P Brooks

Human mutation, Vol.31(6), pp.E1472-E1483

06/2010

DOI: 10.1002/humu.21268

PMCID: PMC2952391

PMID: 20513135

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Abstract

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.

Mutation

Leber Congenital Amaurosis - pathology

Basic-Leucine Zipper Transcription Factors - metabolism

Homeodomain Proteins - metabolism

Humans

Molecular Sequence Data

Infant

Trans-Activators - chemistry

Genes, Dominant

Base Sequence

Trans-Activators - genetics

Female

Eye Proteins - genetics

Protein Structure, Tertiary

Cell Line

Models, Molecular

Leber Congenital Amaurosis - genetics

Basic-Leucine Zipper Transcription Factors - genetics

Homeodomain Proteins - chemistry

Blotting, Western

Homeodomain Proteins - genetics

Sequence Homology, Amino Acid

Eye Proteins - metabolism

Protein Binding

Protein Conformation

Trans-Activators - metabolism

Details

Title: Subtitle: Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL
Creators: Lorenzo L Nichols II - National Institutes of Health
Ramakrishna P Alur
Elangovan Boobalan
Yuri V Sergeev
Rafael C Caruso
Edwin M Stone
Anand Swaroop
Mary A Johnson
Brian P Brooks
Resource Type: Journal article
Publication Details: Human mutation, Vol.31(6), pp.E1472-E1483
DOI: 10.1002/humu.21268
PMID: 20513135
PMCID: PMC2952391
NLM abbreviation: Hum Mutat
ISSN: 1059-7794
eISSN: 1098-1004
Publisher: United States
Grant note: ZIA EY000479-01 / Intramural NIH HHS
Language: English
Date published: 06/2010
Academic Unit: Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9983980010002771

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