The authors report that they have identified in three autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) kindreds two missense mutations in the CAPN5 gene that encodes calpain-5, an ancient calcium activated cysteine protease present in retinal photoreceptors. Previously, this same group mapped the gene locus for ADNIV to the long arm of chromosome 11 (11q13) in one family.
This is a seminal article on the molecular etiology of a retinal inflammatory condition that may be mistaken for retinitis pigmentosa with retinal neovascularization, and the first article using genomics and proteomics to clearly identify the specific molecular cause of autoimmune eye disease.
ADNIV is an autoimmune true uveitic masquerade syndrome that can mimic uveitis, retinitis pigmentosa, and proliferative diabetic retinopathy and progresses to blindness. Understanding ADNIV pathogenesis could help us to understand the pathogenesis of the conditions it mimics.
The authors first performed linkage analysis based on their previous work to make sure all probands in the three families had same 11q13 mutation. This was confirmed.
Using high-resolution single nucleotide polymorphism sequencing, they narrowed the mutation down to a six megabases known to contain 86 genes. They then isolated the abnormal gene to a single nucleotide substitution in exon 6 where a guanine was changed to a thymine in two families, and a second variant in an adjacent codon in exon 6 where a thymine to cytosine change was present. These two variants resulted in a defective calpain-5 when 3-D reconstruction of the proteins sequenced from the abnormal exons were evaluated.
The authors found using antibodies to calpain-5 that this rotease was strongly expressed in photoreceptors. In tissue culture, normal calapain-5 is found near the cell surface, but in ADNIV-causing mutations, it seems to be found in the cytoplasm due to its altered membrane binding property. This loose protease probably results in cell destruction, mediation of inflammation, and angiogenesis.
Calpain abnormalities have been implicated in a wide range of conditions, including cancer, Alzheimer's disease, multiple sclerosis, cataract, diabetes, and limb-girdle muscular dystrophy. Understanding the role of these mutations in uveitis may result in a completely different approach to preventing end-organ damage from inflammation and may explain paraneoplastic diseases.