Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration

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 CAP...

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Bibliographic Details
Published in:PLoS genetics 2012-10, Vol.8 (10), p.e1003001-e1003001
Main Authors: Mahajan, Vinit B, Skeie, Jessica M, Bassuk, Alexander G, Fingert, John H, Braun, Terry A, Daggett, Heather T, Folk, James C, Sheffield, Val C, Stone, Edwin M
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Autoimmunity
Base Sequence
Calpain
Calpain - chemistry
Calpain - genetics
Cell Line
Cells, Cultured
Choroid Diseases - genetics
Choroid Diseases - pathology
Diabetes
Diabetic retinopathy
Exome
Exons
Eye diseases
Eye Diseases, Hereditary - genetics
Eye Diseases, Hereditary - pathology
Eyes & eyesight
Female
Gene Expression
Gene mutations
Genes
Genetic aspects
Genetic Linkage
Genotype & phenotype
Glaucoma
Health aspects
Hemorrhage
Humans
Male
Medicine
Models, Molecular
Molecular Sequence Data
Mutation
Neovascularization
Pedigree
Phenotype
Photoreceptor Cells, Vertebrate - metabolism
Photoreceptor Cells, Vertebrate - pathology
Photoreceptors
Physiological aspects
Protein Conformation
Protein Transport
Proteins
Retina
Retinal Degeneration - genetics
Retinal Degeneration - pathology
Sequence Alignment
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Description
Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1003001