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

Vinit B Mahajan; Jessica M Skeie; Alexander G Bassuk; John H Fingert; Terry A Braun; Heather T Daggett; James C Folk; Val C Sheffield; Edwin M Stone

doi:10.1371/journal.pgen.1003001

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

Journal article

Open access

Peer reviewed

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

Vinit B Mahajan, Jessica M Skeie, Alexander G Bassuk, John H Fingert, Terry A Braun, Heather T Daggett, James C Folk, Val C Sheffield and Edwin M Stone

PLoS genetics, Vol.8(10), pp.e1003001-e1003001

2012

DOI: 10.1371/journal.pgen.1003001

PMCID: PMC3464205

PMID: 23055945

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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.

Exons

Humans

Molecular Sequence Data

Male

Calpain - genetics

Calpain - chemistry

Exome

Base Sequence

Female

Choroid Diseases - genetics

Genetic Linkage

Amino Acid Sequence

Cell Line

Gene Expression

Eye Diseases, Hereditary - pathology

Retinal Degeneration - genetics

Cells, Cultured

Models, Molecular

Eye Diseases, Hereditary - genetics

Protein Transport

Phenotype

Sequence Alignment

Choroid Diseases - pathology

Pedigree

Protein Conformation

Mutation

Photoreceptor Cells, Vertebrate - metabolism

Retinal Degeneration - pathology

Photoreceptor Cells, Vertebrate - pathology

Details

Title: Subtitle: Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration
Creators: Vinit B Mahajan - Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA
Jessica M Skeie
Alexander G Bassuk
John H Fingert
Terry A Braun
Heather T Daggett
James C Folk
Val C Sheffield
Edwin M Stone
Resource Type: Journal article
Publication Details: PLoS genetics, Vol.8(10), pp.e1003001-e1003001
DOI: 10.1371/journal.pgen.1003001
PMID: 23055945
PMCID: PMC3464205
NLM abbreviation: PLoS Genet
ISSN: 1553-7390
eISSN: 1553-7404
Publisher: United States
Grant note: R01EY016822 / NEI NIH HHS\nF32 EY022280 / NEI NIH HHS\nR01 EY016822 / NEI NIH HHS\nHoward Hughes Medical Institute\nR01NS064159 / NINDS NIH HHS\nK08EY020530 / NEI NIH HHS\nK08 EY020530 / NEI NIH HHS\nR01 EY024665 / NEI NIH HHS
Language: English
Date published: 2012
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Neurology; Electrical and Computer Engineering; Stead Family Department of Pediatrics; The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; Medical Genetics and Genomics; Neurology (Pediatrics); Ophthalmology and Visual Sciences
Record Identifier: 9983980055602771

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