CAPN5 – CAPN5-related Vitreoretinopathy

The association between CAPN5 (HGNC:1482) and CAPN5-related vitreoretinopathy (MONDO:0100450) is supported by multiple independent case reports, family-based studies, and robust functional evaluations. In several reports, autosomal dominant inheritance has been consistently observed, with affected individuals showing inflammatory vitreoretinal degeneration manifested by features such as exudative retinal detachment, uveitis, and retinal neovascularization (PMID:23861576).

Genetic evidence arises from identification of distinct pathogenic variants found in unrelated probands. For instance, a recurrent variant, c.731T>C (p.Leu244Pro), was identified in one study and is representative of the mutational spectrum, which further includes other missense mutations across CAPN5. Multiple families demonstrated segregation of CAPN5 mutations with the disease phenotype, with at least five affected individuals in one pedigree (PMID:37782277) and additional de novo cases further supporting the autosomal dominant mode of inheritance (PMID:30986125).

The genetic evidence is bolstered by the observation of at least five distinct pathogenic alleles identified in more than nine probands (PMID:25856303, PMID:37782277). Detailed structural modeling and segregation analyses further corroborate that these mutations disrupt the calcium-sensitive gating loop in calpain-5, leading to its hyperactivation.

Functional studies provide strong experimental support. In vivo models, including knock‑in mice expressing the human CAPN5-R243L variant, recapitulate hallmark features of the disease by demonstrating retinal degeneration, inflammatory cell infiltration, and aberrant protease activity in the retina (PMID:24381307, PMID:25994508). These studies confirm that the disease mechanism is mediated by a gain‑of‑function, where mutant CAPN5 elevates proteolytic activity and triggers downstream inflammatory cascades.

Integration of the genetic and functional assessments establishes a coherent narrative for CAPN5-related vitreoretinopathy. The convergence of multiple independent genetic studies showing autosomal dominant segregation and functional data demonstrating enhanced calpain‑5 activity supports a strong gene‑disease association. Additional evidence from multi‑patient studies exceeding standard scoring thresholds further underscores its clinical utility in guiding diagnostic and therapeutic decisions.

Key Take‑home: CAPN5 mutations, typified by the c.731T>C (p.Leu244Pro) allele, robustly predict autosomal dominant vitreoretinopathy and offer a critical target for diagnostic stratification and future treatment interventions.

References

• Clinical Ophthalmology (Auckland, N.Z.) • 2013 • Lymphocyte infiltration in CAPN5 autosomal dominant neovascular inflammatory vitreoretinopathy PMID:23861576
• PLoS One • 2015 • Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment PMID:25856303
• Investigative Ophthalmology & Visual Science • 2018 • Photoreceptor Cell-Derived CAPN5 Regulates Retinal Pigment Epithelium Cell Proliferation Through Direct Regulation of SLIT2 Cleavage PMID:29610848
• Ocular Immunology and Inflammation • 2019 • Early Onset Neovascular Inflammatory Vitreoretinopathy Due to a De Novo CAPN5 Mutation: Report of a Case PMID:30986125
• Human Mutation • 2019 • CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials PMID:31403230
• Ophthalmic Genetics • 2023 • Autosomal dominant neovascular inflammatory vitreoretinopathy with CAPN5 c.731T > C gene mutation; clinical management of a family cohort and review of the literature PMID:37782277
• Human Molecular Genetics • 2014 • Functional validation of a human CAPN5 exome variant by lentiviral transduction into mouse retina PMID:24381307
• Human Molecular Genetics • 2015 • CAPN5 mutation in hereditary uveitis: the R243L mutation increases calpain catalytic activity and triggers intraocular inflammation in a mouse model PMID:25994508

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