@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 {2047, title = {Therapeutic Window for Phosphodiesterase 6-Related Retinitis Pigmentosa.}, journal = {JAMA Ophthalmol}, volume = {137}, year = {2019}, month = {2019 Jun 01}, pages = {679-680}, keywords = {Cone-Rod Dystrophies, Cyclic Nucleotide Phosphodiesterases, Type 6, Eye Proteins, Follow-Up Studies, Humans, Mutation, Retinitis Pigmentosa}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2018.6381}, author = {Wang, Nan-Kai and Mahajan, Vinit B and Tsang, Stephen H} } @article {641, title = {Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 10 01}, pages = {4244-4255}, abstract = {

Retinitis pigmentosa (RP) is an incurable neurodegenerative condition featuring photoreceptor death that leads to blindness. Currently, there is no approved therapeutic for photoreceptor degenerative conditions like RP and atrophic age-related macular degeneration (AMD). Although there are promising results in human gene therapy, RP is a genetically diverse disorder, such that gene-specific therapies would be practical in a small fraction of patients with RP. Here, we explore a non-gene-specific strategy that entails reprogramming photoreceptors towards anabolism by upregulating the mechanistic target of rapamycin (mTOR) pathway. We conditionally ablated the tuberous sclerosis complex 1 (Tsc1) gene, an mTOR inhibitor, in the rods of the Pde6bpreclinical RP mouse model and observed, functionally and morphologically, an improvement in the survival of rods and cones at early and late disease stages. These results elucidate the ability of reprogramming the metabolome to slow photoreceptor degeneration. This strategy may also be applicable to a wider range of neurodegenerative diseases, as enhancement of nutrient uptake is not gene-specific and is implicated in multiple pathologies. Enhancing anabolism promoted neuronal survival and function and could potentially benefit a number of photoreceptor and other degenerative conditions.

}, keywords = {Animals, Cell Death, Cellular Reprogramming, Cone-Rod Dystrophies, Disease Models, Animal, Humans, Macular Degeneration, Metabolism, Mice, Photoreceptor Cells, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Retinitis Pigmentosa, TOR Serine-Threonine Kinases, Tumor Suppressor Proteins}, issn = {1460-2083}, doi = {10.1093/hmg/ddw256}, author = {Zhang, Lijuan and Justus, Sally and Xu, Yu and Pluchenik, Tamara and Hsu, Chun-Wei and Yang, Jin and Duong, Jimmy K and Lin, Chyuan-Sheng and Jia, Yading and Bassuk, Alexander G and Mahajan, Vinit B and Tsang, Stephen H} }