Two Novel CAPN5 Variants Associated with Mild and Severe Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy Phenotypes

Abstract

Purpose: We report two new CAPN5 mutations associated with a phenotype of Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy. Methods: We performed next generation sequencing in two patients with ADNIV phenotype; the variants identified were explored further. Results: Patient 1 was heterozygous for CAPN5 c.799G>A, p.(Gly267Ser). Patient 2 was heterozygous for CAPN5 c.1126G>A, p.(Gly376Ser). Both amino acids are highly conserved across species. Patient 1 had a severe phenotype and his mutation lies within the protein's catalytic domain. Patient 2 had a mild phenotype and her mutation is the first ADNIV-causing mutation to be described in the regulatory domain of Calpain-5. Conclusions: Our findings potentially add two new ADNIV-causing CAPN5 mutations to the three previously described. We recommend CAPN5 genetic testing in all patients with a possible ADNIV phenotype, to develop our understanding of Calpain-5; a protein which could potentially provide therapeutically accessible targets for the treatment of many leading causes of blindness.

Keywords: ADNIV; Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy; CALPAIN-5; CAPN5; UVEITIS.

Figure 1. Two Novel CAPN5 mutations identified associated with ADNIV

A. Calpain-5 is a 640 amino acid, 73 kDa protein composed of four domains. The mutations previously described are located in catalytic domain IIb. B. P1 mutation CAPN5 c.799G>A missense change equivalent to p.(Gly267Ser) or replacement of hydrophobic glycine for serine which is polar at the corresponding amino acid position. C. P2 mutation CAPN5 c.1126G>A missense change equivalent to p.(Gly376Ser). This is the first ADNIV- causing mutation identified in the regulatory domain of the protein.

Figure 2. ADNIV Phenotype

A. Patient 1 has a severe phenotype: optomap shows bilateral vasoproliferative vitreoretinal pathology. B. Patient 2 has a mild phenotype: colour photographs show patchy areas of retinal pigmentary change.

Figure 3. Patient 2 Fundus Fluorescein angiogram

Fluorescein angiography reveals patchy asymmetrical pigmentary retinopathy and a small area of periphlebitis in the left eye (white arrow).

Figure 4. The novel CAPN5 mutated residues are highly conserved amongst species

Alignment of calpain-5 orthologs show high evolutionary conservation of both patients’ CAPN5 mutations. A. Patient 1 nucleotide change position Gly267 is indicated in green B. Patient 2 nucleotide change position Gly 376 is indicated in red.