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 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.
Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA.
Vinit B
VB
Mahajan
Jessica M
JM
Skeie
Alexander G
AG
Bassuk
John H
JH
Fingert
Terry A
TA
Braun
Heather T
HT
Daggett
James C
JC
Folk
Val C
VC
Sheffield
Edwin M
EM
Stone
D000595:Amino Acid Sequence; D001483:Base Sequence; D002154:Calpain / Q000737:chemistry / Q000235:genetics*; D002460:Cell Line; D002478:Cells, Cultured; D015862:Choroid Diseases / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005091:Exons; D015785:Eye Diseases, Hereditary / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation; D021381:Protein Transport; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D016415:Sequence Alignment
D002154:Calpain; C494426:Capn5 protein, human