@article {1921, title = {New COL6A6 Variant Causes Autosomal Dominant Retinitis Pigmentosa in a Four-Generation Family.}, journal = {Invest Ophthalmol Vis Sci}, volume = {63}, year = {2022}, month = {2022 Mar 02}, pages = {23}, abstract = {

Purpose: To report that variants in the gene for a large lamina basal component protein, COL6A6 (collagen type VI alpha 6 chain, Col6α6), linked to chromosome 3p22.1 causes retinitis pigmentosa (RP) in patients with autosomal dominant transmission (adRP).

Methods: A positional-cloning approach, whole exome sequencing, and modeling were used. The proband and several affected family members have been phenotyped and followed for over 12 years.

Results: A heterozygous missense variant, c.509C\>G (p. Ser170Cys) in exon 2 of COL6A6 (comprised of 36 exons and 2236 amino acids), was observed in a four- generation family and is likely to cause the adRP phenotype. It was identified in 10 affected members. All affected family members had a distinct phenotype: late-onset rod cone dystrophy, with good retained visual acuity, until their late 70s. Immunohistochemistry of human retina showed a dot-like signal at the base of the inner segments of photoreceptors and outer plexiform layer (OPL). The structural modeling of the N7 domain of Col6α6 suggests that the mutant might result in the abnormal cellular localization of collagen VI or malformation of collagen fibers resulting in the loss of its unique filament structure.

Conclusions: COL6A6 is widely expressed in human tissues and evolutionary conserved. It is thought to interact with a range of extracellular matrix components. Our findings suggest that this form of RP has long-term useful central visual acuity and a mild progression, which are important considerations for patient counseling.

}, keywords = {Collagen Type VI, Cone-Rod Dystrophies, Exons, Humans, Mutation, Missense, Pedigree, Retinitis Pigmentosa}, issn = {1552-5783}, doi = {10.1167/iovs.63.3.23}, author = {Vaclavik, Veronika and Tiab, Leila and Sun, Young Joo and Mahajan, Vinit B and Moulin, Alexandre and Allaman-Pillet, Nathalie and Munier, Francis L and Schorderet, Daniel F} } @article {655, title = {CRISPR Repair Reveals Causative Mutation in a Preclinical Model of Retinitis Pigmentosa.}, journal = {Mol Ther}, volume = {24}, year = {2016}, month = {2016 08}, pages = {1388-94}, abstract = {

Massive parallel sequencing enables identification of numerous genetic variants in mutant organisms, but determining pathogenicity of any one mutation can be daunting. The most commonly studied preclinical model of retinitis pigmentosa called the "rodless" (rd1) mouse is homozygous for two mutations: a nonsense point mutation (Y347X) and an intronic insertion of a leukemia virus (Xmv-28). Distinguishing which mutation causes retinal degeneration is still under debate nearly a century after the discovery of this model organism. Here, we performed gene editing using the CRISPR/Cas9 system and demonstrated that the Y347X mutation is the causative variant of disease. Genome editing in the first generation produced animals that were mosaic for the corrected allele but still showed neurofunction preservation despite low repair frequencies. Furthermore, second-generation CRISPR-repaired mice showed an even more robust rescue and amelioration of the disease. This predicts excellent outcomes for gene editing in diseased human tissue, as Pde6b, the mutated gene in rd1 mice, has an orthologous intron-exon relationship comparable with the human PDE6B gene. Not only do these findings resolve the debate surrounding the source of neurodegeneration in the rd1 model, but they also provide the first example of homology-directed recombination-mediated gene correction in the visual system.

}, keywords = {Animals, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Cas Systems, Cyclic Nucleotide Phosphodiesterases, Type 6, Disease Models, Animal, DNA Repair, Electroretinography, Exons, Gene Editing, Genetic Loci, Homologous Recombination, Mice, Mice, Transgenic, Mutation, Photoreceptor Cells, Vertebrate, Retinal Degeneration, Retinitis Pigmentosa, RNA, Guide}, issn = {1525-0024}, doi = {10.1038/mt.2016.107}, author = {Wu, Wen-Hsuan and Tsai, Yi-Ting and Justus, Sally and Lee, Ting-Ting and Zhang, Lijuan and Lin, Chyuan-Sheng and Bassuk, Alexander G and Mahajan, Vinit B and Tsang, Stephen H} } @article {115, title = {Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1003001}, abstract = {

Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is an autoimmune condition of the eye that sequentially mimics uveitis, retinitis pigmentosa, and proliferative diabetic retinopathy as it progresses to complete blindness. We identified two different missense mutations in the CAPN5 gene in three ADNIV kindreds. CAPN5 encodes calpain-5, a calcium-activated cysteine protease that is expressed in retinal photoreceptor cells. Both mutations cause mislocalization from the cell membrane to the cytosol, and structural modeling reveals that both mutations lie within a calcium-sensitive domain near the active site. CAPN5 is only the second member of the large calpain gene family to cause a human Mendelian disorder, and this is the first report of a specific molecular cause for autoimmune eye disease. Further investigation of these mutations is likely to provide insight into the pathophysiologic mechanisms of common diseases ranging from autoimmune disorders to diabetic retinopathy.

}, keywords = {Amino Acid Sequence, Base Sequence, Calpain, Cell Line, Cells, Cultured, Choroid Diseases, Exome, Exons, Eye Diseases, Hereditary, Female, Gene Expression, Genetic Linkage, Humans, Male, Models, Molecular, Molecular Sequence Data, Mutation, Pedigree, Phenotype, Photoreceptor Cells, Vertebrate, Protein Conformation, Protein Transport, Retinal Degeneration, Sequence Alignment}, author = {Mahajan, Vinit B and Skeie, Jessica M and Bassuk, Alexander G and Fingert, John H and Braun, Terry A and Daggett, Heather T and Folk, James C and Sheffield, Val C and Stone, Edwin M} }