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Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa |
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| Authors: | James S. Friedman,Naushin Waseem,Matthew J. Brooks,Debra Breuer,Daniel S. Krauth,Lori S. Sullivan,Lotta Grä nse,Edward H. Trager,Dianna Hughbanks-Wheaton,Noor M. Ghiasvand,Christina F. Chakarova,Harald H.H. Gö ring,David G. Birch,Yang Fann,Stephen P. Daiger,Sten André asson |
| Affiliation: | 1 Neurobiology-Neurodegeneration & Repair Laboratory (N-NRL), National Eye Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA 2 Human Genetic Center, The University of Texas Health Science Center, Houston, TX 77030, USA 3 Department of Molecular Genetics, Institute of Ophthalmology, London, EC1 9EL, UK 4 Bioinformatics Section, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA 5 Department of Ophthalmology, Lund University Hospital, S-221 85 Lund, Sweden 6 Department of Ophthalmology, University of Michigan, Ann Arbor, MI 48105, USA 7 Retina Foundation of the Southwest, Dallas, TX 75231, USA 8 Department of Laboratory Medicine, Lund University, S-221 85 Lund, Sweden 9 Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX 78227, USA 10 Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI 48105, USA 11 Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA |
| Abstract: | Retinitis pigmentosa (RP) refers to a genetically heterogeneous group of progressive neurodegenerative diseases that result in dysfunction and/or death of rod and cone photoreceptors in the retina. So far, 18 genes have been identified for autosomal-dominant (ad) RP. Here, we describe an adRP locus (RP42) at chromosome 7p15 through linkage analysis in a six-generation Scandinavian family and identify a disease-causing mutation, c.449G→A (p.S150N), in exon 6 of the KLHL7 gene. Mutation screening of KLHL7 in 502 retinopathy probands has revealed three different missense mutations in six independent families. KLHL7 is widely expressed, including expression in rod photoreceptors, and encodes a 75 kDa protein of the BTB-Kelch subfamily within the BTB superfamily. BTB-Kelch proteins have been implicated in ubiquitination through Cullin E3 ligases. Notably, all three putative disease-causing KLHL7 mutations are within a conserved BACK domain; homology modeling suggests that mutant amino acid side chains can potentially fill the cleft between two helices, thereby affecting the ubiquitination complexes. Mutations in an identical region of another BTB-Kelch protein, gigaxonin, have previously been associated with giant axonal neuropathy. Our studies suggest an additional role of the ubiquitin-proteasome protein-degradation pathway in maintaining neuronal health and in disease. |
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