A novel de novo CAPN5 mutation in a patient with inflammatory vitreoretinopathy, hearing loss, and developmental delay

Abstract

Mutations that activate the protease calpain-5 (CAPN5) cause a nonsyndromic adult-onset autoinflammatory eye disease characterized by uveitis, altered synaptic signaling, retinal degeneration, neovascularization, and intraocular fibrosis. We describe a pediatric patient with severe inflammatory vitreoretinopathy accompanied by hearing loss and developmental delay associated with a novel, de novo CAPN5 missense mutation (c.865C>T, p.Arg289Trp) that shows greater hyperactivation of the calpain protease, indicating a genotype–phenotype correlation that links mutation severity to proteolytic activity and the possibility of earlier onset syndromic disease with auditory and neurological abnormalities.

CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials

“…PPI reflects the ability of the mouse to integrate and inhibit sensory information, and the failure to do so has been shown in a variety of human neurological disorders, such as Huntington's disease and autism (Cadenhead, Carasso, Swerdlow, Geyer, & Braff, ; Ouagazzal, Grottick, Moreau, & Higgins, ; Ouagazzal, Jenck, & Moreau, ; Swerdlow, Braff, & Geyer, ). This correlates with human ADNIV patients, as recently we have shown that one GOF mutation, p.Arg289Trp causes a syndromic form of NIV with the presentation of hearing loss and developmental delay (Velez, et al, ). In the knockout mice, this startle reflex was slightly more significant in males (112 of 3,080; 3.64%) compared to females (97 of 3,070; 3.16%), although it did affect both genders (Blake et al, ).…”

“…A model of the full‐length CAPN5 protein was generated using a domain assembly approach. The structure of the protease core domain was modeled off the crystal structure for CAPN9 (PDB: 1ZIV; Davis et al, ) as previously described (Bassuk et al, ; Gakhar et al, ; Velez et al, ). The structure of CAPN5's CBSW domain (DIII) was modeled in the MODELLER 9.14 (Eswar et al, ) program using the crystal structure of human CAPN2 (Strobl et al, ) as a template (PDB: 1KFU, 32% identity, 95% sequence coverage).…”

“…Most patients suffer nonsyndromic vision loss due to severe autoinflammatory uveitis, retinal neovascularization, and retinal degeneration. In the syndromic form, there is also hearing loss and developmental delay (Velez et al, ). CAPN5 encodes the calcium‐activated cysteine protease calpain‐5, found to be ubiquitously expressed in the body, including in the eye (Schaefer et al, ).…”

Structural Insights into the Unique Activation Mechanisms of a Non-classical Calpain and Its Disease-Causing Variants

“…We recently identified a de novo CAPN5 mutation (p.R289W) in a pediatric patient with early-onset severe vitreoretinopathy, optic neuritis, and hearing loss. This mutation, which is located on a different loop, displayed higher enzymatic activity than the previously identified mutations, suggesting a correlation between the level of protease hyperactivity and disease severity (Velez et al, 2018).…”

“…This subtle change in k cat is biologically meaningful due to the slow timescale of NIV disease progression. Patients are not born with the disease, and NIV often takes 20 or more years to develop (Bassuk et al, 2015;Mahajan et al, 2012;Velez et al, 2017Velez et al, , 2018Wert et al, 2015). DSF and IWF results for CAPN5 p.G267S were indistinguishable from WT (data not shown) suggesting its hyperactivity was independent of Ca 2+ -induced conformational changes or stabilization.…”