@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 {699, title = {Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0122352}, abstract = {

CAPN5 mutations have been linked to autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a blinding autoimmune eye disease. Here, we link a new CAPN5 mutation to ADNIV and model the three-dimensional structure of the resulting mutant protein. In our study, a kindred with inflammatory vitreoretinopathy was evaluated by clinical eye examinations, DNA sequencing, and protein structural modeling to investigate the disease-causing mutation. Two daughters of an affected mother demonstrated symptoms of stage III ADNIV, with posterior uveitis, cystoid macular edema, intraocular fibrosis, retinal neovascularization, retinal degeneration, and cataract. The women also harbored a novel guanine to thymine (c.750G\>T, p.Lys250Asn) missense mutation in exon 6 of CAPN5, a gene that encodes a calcium-activated cysteine protease, calpain-5. Modeling based on the structures of all known calpains revealed the mutation falls within a calcium-sensitive flexible gating loop that controls access to the catalytic groove. Three-dimensional modeling placed the new mutation in a region adjacent to two previously identified disease-causing mutations, all three of which likely disrupt hydrogen bonding within the gating loop, yielding a CAPN5 with altered enzymatic activity. This is the third case of a CAPN5 mutation leading to inherited uveitis and neovascular vitreoretinopathy, suggesting patients with ADNIV features should be tested for CAPN5 mutations. Structural modeling of novel variants can be used to support mechanistic consequences of the disease-causing variants.

}, keywords = {Base Sequence, Calpain, Computational Biology, DNA Primers, Female, Fluorescein Angiography, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Pedigree, Phenotype, Protein Conformation, Retinal Detachment, Sequence Analysis, DNA, Tomography, Optical Coherence, Uveitis, Vitreoretinopathy, Proliferative}, issn = {1932-6203}, doi = {10.1371/journal.pone.0122352}, author = {Bassuk, Alexander G and Yeh, Steven and Wu, Shu and Martin, Daniel F and Tsang, Stephen H and Gakhar, Lokesh and Mahajan, Vinit B} } @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} } @article {157, title = {Collagen XVIII mutation in Knobloch syndrome with acute lymphoblastic leukemia.}, journal = {American journal of medical genetics. Part A}, volume = {152A}, year = {2010}, month = {2010 Nov}, pages = {2875-9}, abstract = {

Knobloch syndrome (KNO) is caused by mutations in the collagen XVIII gene (COL18A1) and patients develop encephalocele and vitreoretinal degeneration. Here, we report an El Salvadorian family where two sisters showed features of KNO. One of the siblings also developed acute lymphoblastic leukemia. DNA sequencing of COL18A1 revealed a homozygous, 2-bp deletion (c3514-3515delCT) in exon 41, which leads to abnormal collagen XVIII and deficiency of its proteolytic cleavage product endostatin. KNO patients with mutations in COL18A1 may be at risk for endostatin-related conditions including malignancy.

}, keywords = {Base Sequence, Child, Child, Preschool, Collagen Type XVIII, DNA Mutational Analysis, Encephalocele, Eye Abnormalities, Family, Female, Humans, Infant, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Mutation, Pedigree, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Retinal Detachment}, author = {Mahajan, Vinit B and Olney, Ann Haskins and Garrett, Penny and Chary, Ajit and Dragan, Ecaterina and Lerner, Gary and Murray, Jeffrey and Bassuk, Alexander G} } @article {173, title = {A new macular dystrophy with anomalous vascular development, pigment spots, cystic spaces, and neovascularization.}, journal = {Archives of ophthalmology}, volume = {127}, year = {2009}, month = {2009 Nov}, pages = {1449-57}, abstract = {

To clinically phenotype an inherited macular dystrophy with peculiar intraretinal pigment spots, cysts, and hemorrhage in a 24-year-old female proband and her family.

}, keywords = {Adolescent, Adult, Amblyopia, Child, Child, Preschool, Cysts, Electroretinography, Female, Fluorescein Angiography, Humans, Macular Degeneration, Male, Middle Aged, Pedigree, Phenotype, Retinal Hemorrhage, Retinal Neovascularization, Retinal Pigment Epithelium, Retinal Vessels, Strabismus, Tomography, Optical Coherence, Visual Acuity, Young Adult}, author = {Mahajan, Vinit B and Russell, Stephen R and Stone, Edwin M} }